Myelodysplastic Syndromes: An Update on Pathophysiology and Management

*Wanxing Chai-Ho and Gary J. Schiller*

## **Abstract**

Myelodysplastic syndromes (MDS) comprise a set of clonal hematopoietic stem cell (HSC) disorders characterized by ineffective hematopoiesis that manifest as cytopenia of variable severity. The result often is an increased risk of infection, transfusion dependence, and a potential to transform to acute myeloid leukemia (AML). For the past decade, hypomethylating agents remain the only FDA-approved therapy. Given that MDS is more prevalent in the elderly who often have comorbid conditions, supportive care remains the mainstay of therapy. Curative treatments are restricted to younger, healthy individuals with histocompatible-matched donors for allogeneic transplant able to tolerate more intensive chemotherapeutic treatment. Understanding of the pathophysiology of MDS advanced over the past decade, which leads to an increasing array of new agents under clinical investigation. This review focuses on our recent enhanced understanding of MDS molecular biology, and promising novel agents that go beyond the hypomethylating agent.

**Keywords:** myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), bone marrow transplant, hypomethylating agent, somatic mutation

### **1. Introduction**

The myelodysplastic syndromes (MDS) comprise an heterogeneous group of malignant hematopoietic stem cell disorders characterized by dysplastic and ineffective blood cell production and a variable risk of transformation to acute leukemia. Based on the United States Surveillance, Epidemiology, and End Results (SEER) Program, the incidence of MDS is about 4.1–4.6 cases per 100,000 population per year, with approximately 86% of patients aged ≥60 years at time of diagnosis (median age 76 years). The incidence rate is higher in men than women. [1] The prevalence is slightly lower in Europe with reported 1.24–3.7 cases per 100,000 population per year, also with observed male predominance.[2, 3] With an aging population and improved awareness of disease, it is likely that the number of new patients diagnosed with MDS each year will increase in the future.

Pathogenesis of MDS is incompletely understood. Studies have revealed age, male gender, alcohol, cigarette smoking, ionizing radiation, chemotherapy such as alkylating agents and topoisomerase II inhibitor, immunosuppressive therapy, viral infection, benzene and other environmental/occupational exposures as possible implicating factors. [4–8] However, disease caused by these risk factors are estimated to account for only 20–30% of cases, which are described as secondary MDS, with remainders as primary MDS [4]. The major subsets of secondary MDS are therapyrelated MDS (t-MDS) and MDS with predisposition to familial myeloid neoplasm.

The risk for MDS and AML is increased in certain familial predisposition syndromes, such as inherited bone marrow failure disorders like Diamond-Blackfan syndrome, Fanconi anemia, dyskeratosis congenital, Shwachman-Diamond syndrome, and Down syndrome, Noonan syndrome/Noonan syndrome-like disorders and neurofibromatosis [9]. Accurate diagnosis and recognition of these syndromic disorders allows opportunities to improve clinical care. Genetic counseling should be offered to family members of affected individual. One should avoid using heterozygous sibling as bone marrow transplant donor. Recently, a growing number of germline mutations including CEBPA, DDX41, ANKRD26, ETV6, GATA2, RUNX1 were identified to associate with familial thrombocytopenia and development of MDS and acute leukemia in up to 40% of patients [10, 11]. Special attention should be noted that many patients with familial MDS and acute leukemia predisposition syndromes develop disease in adulthood rather than childhood. To increase awareness of this entity of disease, myeloid neoplasm with above mentioned germline predisposition was incorporated into the updated WHO 2016 classification [12].

### **2. Diagnosis**

#### **2.1 Clinical presentation**

MDS usually presents as cytopenia in one or more lineage. Fatigue, dyspnea on exertion, infection, easy bruising or bleeding are the most common symptoms. Lymphadenopathy and hepatosplenomegaly are infrequent and should raise suspicion for chronic myelomonocytic leukemia (CMML) [13, 14]. It has been estimated that various autoimmune features such as subacute vasculitis, fever, arthritis, peripheral edema, and pulmonary infiltrates, may be present in up to 10% of patients [15–18]. Certain autoimmune syndromes have correlated with distinct cytogenetic abnormalities; including Behcet's disease with trisomy 8, Sweet's syndrome and pyoderma gangrenosum with del(5q) [19]. Acquired hemoglobin H disease has been documented in approximately 8% of cases of MDS [20–22]. An acquired somatic mutation of ATRX, an X-linked gene encoding a chromatin-associated protein, has been linked to this entity, [21] as have acquired deletions of the alpha globin loci.

#### **2.2 Pathology evaluation and WHO criteria**

Bone marrow aspiration and biopsy are critical to the diagnosis of MDS. In general, the marrow is normo- or hypercellular due to ineffective hematopoiesis. However, up to 20% of MDS patients have hypocellular marrow, making it difficult to distinguish from aplastic anemia or paroxysmal nocturnal hematuria [23, 24]. Dysplastic neutrophils are commonly found in the peripheral blood smear. These cells may demonstrate reduced segmentation, increased size, the so-called pseudo-Pelger-Huet cell [25], often accompanied by reduced or absent granulation [26], and are associated with del(17)p [27]. Hypersegmentation with greater than 5 nuclear lobes is another feature of neutrophil dysplasia [28]. Red cells are usually normocytic or macrocytic, although ring sideroblasts, ovalomacrocytosis, teardrops, stomatocytes or acanthocytes may be seen [28]. Platelet morphology is usually normal, but micromegakaryocytes, mononuclear megakaryocytes, dumbbell-shaped nuclei, multinuclearity with multiple isolated nuclei ("Pawn ball" changes) may be seen [29].

**65**

**Table 1.**

del(9q) idic(X)(q13)

*Health Organization 2008 and 2016 criteria.*

*Myelodysplastic Syndromes: An Update on Pathophysiology and Management*

Classification of MDS has been a challenge. In 1982, the French-American-British (FAB) Cooperative Group published the first seminal classification system that distinguished five subcategories of MDS based on marrow morphological criteria and myeloblasts proportions: refractory anemia, refractory anemia with ring sideroblasts (RARS), refractory anemia with excess of blasts (RAEB), RAEB "in transformation" (RAEB-T), and chronic myelomonocytic leukemia (CMML) [30]. Presence of more than 30% blasts in the bone marrow was defined as AML. In 2001, World Health Organization (WHO) published new classification system on myeloid malignancy with modifications to the FAB system: The diagnosis of AML requires 20% myeloblasts. RAEB-T is classified as AML, and CMML is categorized as a new entity of myeloid neoplasms with both MDS and myeloproliferative features. In addition, MDS with isolated del(5q) is acknowledged as distinctive features in forms of disease with a low blast count, severe anemia and thrombocytosis (5q- syndrome) [31]. The revised 2008 WHO criteria maintained these modifications [32]. In the absence of definitive morphologic features of MDS, MDS-defining cytogenetic abnormalities were included in the diagnostic criteria (**Table 1**). The presence of chromosome 7, Y, or del(20q) does not meet criteria as an

The 2016 revision of WHO (**Table 2**) incorporated rapidly accumulating molecular genetic information into the classification [12]. The same cytogenetic abnormalities listed in the 2008 WHO classification remain MDS-defining in a cytopenic patient. Given recent data showing 1 chromosomal abnormality in addition to the del(5q) poses no adverse effect [33–35], the entity "5q- syndrome" may be diagnosed if there is 1 additional cytogenetic abnormality besides the del(5q), unless that abnormality is monosomy 7 or del(7q). Mutations like SF3B1, TET2, SRSF2, ASXL1, DNMT3A, RUNX1, U2AF1, TP53, and EZH2 can be found in 80–90% MDS patients [36, 37]. Importantly, acquired clonal mutations identical to those seen in MDS can occur in the hematopoietic cells of healthy older individuals without MDS, so-called "clonal hematopoiesis of indeterminate potential" (CHIP), or patients with mild cytopenia but without dysplastic changes or specific cytogenetic and/ or genetic abnormalities considered as presumptive evidence of MDS (idiopathic cytopenia of undetermined significance, ICUS) [38, 39]. Although some CHIP and ICUS subsequently develop MDS, there have not been sufficient data to support using the presence of aforementioned mutations as surrogate diagnostic marker of MDS. Based on the link between ring sideroblasts and an SF3B1 mutation, MDS

**Unbalanced abnormalities Balanced abnormalities** −7 or del(7q) t(11;16)(q23;p13.3) −5 or del(5q) t(3;21)(q26.2;q22.1) i(17q) or t(17p) t(1;3)(p36.3;q21.1) −13 or del(13q) t(2;11)(p21;q23) del(11q) inv(3)(q21q26.2) del(12p) or t(12p) t(6;9)(p23;q34)

*Complex karyotype (3 or more chromosomal abnormalities) involving one or more of the above abnormalities.*

*Recurring chromosomal abnormalities considered as presumptive evidence of MDS in the setting of persistent cytopenia or undetermined origin in the absence of definitive morphologic features of MDS, according to World* 

*DOI: http://dx.doi.org/10.5772/intechopen.82166*

MDS-defining abnormality.

#### *Myelodysplastic Syndromes: An Update on Pathophysiology and Management DOI: http://dx.doi.org/10.5772/intechopen.82166*

Classification of MDS has been a challenge. In 1982, the French-American-British (FAB) Cooperative Group published the first seminal classification system that distinguished five subcategories of MDS based on marrow morphological criteria and myeloblasts proportions: refractory anemia, refractory anemia with ring sideroblasts (RARS), refractory anemia with excess of blasts (RAEB), RAEB "in transformation" (RAEB-T), and chronic myelomonocytic leukemia (CMML) [30]. Presence of more than 30% blasts in the bone marrow was defined as AML.

In 2001, World Health Organization (WHO) published new classification system on myeloid malignancy with modifications to the FAB system: The diagnosis of AML requires 20% myeloblasts. RAEB-T is classified as AML, and CMML is categorized as a new entity of myeloid neoplasms with both MDS and myeloproliferative features. In addition, MDS with isolated del(5q) is acknowledged as distinctive features in forms of disease with a low blast count, severe anemia and thrombocytosis (5q- syndrome) [31]. The revised 2008 WHO criteria maintained these modifications [32]. In the absence of definitive morphologic features of MDS, MDS-defining cytogenetic abnormalities were included in the diagnostic criteria (**Table 1**). The presence of chromosome 7, Y, or del(20q) does not meet criteria as an MDS-defining abnormality.

The 2016 revision of WHO (**Table 2**) incorporated rapidly accumulating molecular genetic information into the classification [12]. The same cytogenetic abnormalities listed in the 2008 WHO classification remain MDS-defining in a cytopenic patient. Given recent data showing 1 chromosomal abnormality in addition to the del(5q) poses no adverse effect [33–35], the entity "5q- syndrome" may be diagnosed if there is 1 additional cytogenetic abnormality besides the del(5q), unless that abnormality is monosomy 7 or del(7q). Mutations like SF3B1, TET2, SRSF2, ASXL1, DNMT3A, RUNX1, U2AF1, TP53, and EZH2 can be found in 80–90% MDS patients [36, 37]. Importantly, acquired clonal mutations identical to those seen in MDS can occur in the hematopoietic cells of healthy older individuals without MDS, so-called "clonal hematopoiesis of indeterminate potential" (CHIP), or patients with mild cytopenia but without dysplastic changes or specific cytogenetic and/ or genetic abnormalities considered as presumptive evidence of MDS (idiopathic cytopenia of undetermined significance, ICUS) [38, 39]. Although some CHIP and ICUS subsequently develop MDS, there have not been sufficient data to support using the presence of aforementioned mutations as surrogate diagnostic marker of MDS. Based on the link between ring sideroblasts and an SF3B1 mutation, MDS


#### **Table 1.**

*Recent Developments in Myelodysplastic Syndromes*

to account for only 20–30% of cases, which are described as secondary MDS, with remainders as primary MDS [4]. The major subsets of secondary MDS are therapyrelated MDS (t-MDS) and MDS with predisposition to familial myeloid neoplasm. The risk for MDS and AML is increased in certain familial predisposition syndromes, such as inherited bone marrow failure disorders like Diamond-Blackfan syndrome, Fanconi anemia, dyskeratosis congenital, Shwachman-Diamond syndrome, and Down syndrome, Noonan syndrome/Noonan syndrome-like disorders and neurofibromatosis [9]. Accurate diagnosis and recognition of these syndromic disorders allows opportunities to improve clinical care. Genetic counseling should be offered to family members of affected individual. One should avoid using heterozygous sibling as bone marrow transplant donor. Recently, a growing number of germline mutations including CEBPA, DDX41, ANKRD26, ETV6, GATA2, RUNX1 were identified to associate with familial thrombocytopenia and development of MDS and acute leukemia in up to 40% of patients [10, 11]. Special attention should be noted that many patients with familial MDS and acute leukemia predisposition syndromes develop disease in adulthood rather than childhood. To increase awareness of this entity of disease, myeloid neoplasm with above mentioned germline predisposition was incorporated into the updated WHO 2016 classification [12].

MDS usually presents as cytopenia in one or more lineage. Fatigue, dyspnea on exertion, infection, easy bruising or bleeding are the most common symptoms. Lymphadenopathy and hepatosplenomegaly are infrequent and should raise suspicion for chronic myelomonocytic leukemia (CMML) [13, 14]. It has been estimated that various autoimmune features such as subacute vasculitis, fever, arthritis,

peripheral edema, and pulmonary infiltrates, may be present in up to 10% of patients [15–18]. Certain autoimmune syndromes have correlated with distinct cytogenetic abnormalities; including Behcet's disease with trisomy 8, Sweet's syndrome and pyoderma gangrenosum with del(5q) [19]. Acquired hemoglobin H disease has been documented in approximately 8% of cases of MDS [20–22]. An acquired somatic mutation of ATRX, an X-linked gene encoding a chromatin-associated protein, has been linked to this entity, [21] as have acquired deletions of the alpha globin loci.

Bone marrow aspiration and biopsy are critical to the diagnosis of MDS. In general, the marrow is normo- or hypercellular due to ineffective hematopoiesis. However, up to 20% of MDS patients have hypocellular marrow, making it difficult to distinguish from aplastic anemia or paroxysmal nocturnal hematuria [23, 24]. Dysplastic neutrophils are commonly found in the peripheral blood smear. These cells may demonstrate reduced segmentation, increased size, the so-called pseudo-Pelger-Huet cell [25], often accompanied by reduced or absent granulation [26], and are associated with del(17)p [27]. Hypersegmentation with greater than 5 nuclear lobes is another feature of neutrophil dysplasia [28]. Red cells are usually normocytic or macrocytic, although ring sideroblasts, ovalomacrocytosis, teardrops, stomatocytes or acanthocytes may be seen [28]. Platelet morphology is usually normal, but micromegakaryocytes, mononuclear megakaryocytes, dumbbell-shaped nuclei, multinuclearity with multiple isolated nuclei ("Pawn

**64**

**2. Diagnosis**

**2.1 Clinical presentation**

**2.2 Pathology evaluation and WHO criteria**

ball" changes) may be seen [29].

*Recurring chromosomal abnormalities considered as presumptive evidence of MDS in the setting of persistent cytopenia or undetermined origin in the absence of definitive morphologic features of MDS, according to World Health Organization 2008 and 2016 criteria.*


#### **Table 2.**

*Classification of myeloid neoplasms and acute leukemia, according to World Health Organization 2016 criteria.*

with ring sideroblasts and multilineage dysplasia, marked thrombocytosis, lacking excess blasts or an isolated del(5q) abnormality is included into the category of MDS with ring sideroblasts, and correlates with a favorable prognosis [40–43].

#### **2.3 Differential diagnosis**

MDS must be distinguished from other marrow dysplasia secondary to reversible causes, such as folate and vitamin B12 deficiency, viral infections (e.g. HIV), antibiotics, benzene, ethanol, or lead poisoning. Other primary bone marrow disorders presenting as pancytopenia, such as aplastic anemia, paroxysmal nocturnal hematuria, hairy cell leukemia, large granular lymphocytic leukemia can be distinguished by marrow morphology, flow cytometry features and gene mutation profile [8].

#### **2.4 Risk stratification**

The natural history of MDS in patients varies. The heterogeneity reflects both known and unknown differences in the pathophysiology of specific disease subtypes and patient related characteristics. Several prognostic scoring systems were developed and validated for MDS patients. In 1996, the International Prognostic Scoring System (IPSS) was developed by the International MDS Risk Analysis Workshop based on FAB classification [44]. Based on percent bone marrow blasts, specific cytogenetic abnormalities, and the number of cell lines involved with dysplasia and cytopenia, individual patient are placed into 4 groups: low,

**67**

**3. Pathogenesis**

*Myelodysplastic Syndromes: An Update on Pathophysiology and Management*

intermediate-1, intermediate-2, and high. The median survival in these four risk categories is 5.7 years for low risk, 3.5 years for intermediate-1 risk, 1.2 years for

In 2012, a revised IPSS (IPSS-R) was developed based upon data from 7012 patients with primary MDS diagnosed using the FAB or WHO classifications [45]. It incorporated new cytogenetic categories [35], and differentially weighed the degree of cytopenias in newly diagnosed patients. Patient age is an optional variable that can be incorporated to predict overall survival, but not evolution to AML. Individual patient was categorized into five risk groups: very low, low, intermediate, high and very high risk, that translates into median survival of 8.8, 5.3, 3.0, 1.6 and 0.8 years respectively. IPSS-R is simple to use, and is perhaps the most commonly used prognostication system today. However, there are several potential limitations to the IPSS-R. Both IPSS and IPSS-R were developed using data from patients who were observed without treatment. While outcomes might be different now that a variety of interventions are available, an analysis of a separate population suggested that the predictive value of the IPSS-R also applies to those treated with lenalidomide and azacitidine. [46] The prognosticating system only considered patients with *de novo* MDS. It is well recognized that patients with secondary MDS are more likely to have shorter survival. Much of this reflects the association between secondary MDS and "unfavorable cytogenetics". In addition, the IPSS-R seems to be most reliable at predicting outcomes at initial disease diagnosis, as the hazards in mortality and leukemia transformation diminishes over time in higherrisk but remains stable in lower-risk patients [47]. With increasing knowledge of MDS clonal genetics, the future risk stratification system might incorporate the prognostic value of mutation profile, which will be discussed in the next section. WHO prognostic scoring system (WPSS) was designed to include information on red blood cell (RBC) transfusion need and cytogenetic information [48]. A subset of patients in the study cohort had data from multiple time points for a time-dependent analysis, therefore had the advantage over the IPSS of being able to

The MD Anderson Cancer Center (MADCC) MDS model was developed based on a retrospective analysis of 856 patients with *de novo* or therapy-related MDS [49]. Age, cytogenetics, degree of anemia and thrombocytopenia, bone marrow blast percentage were identified as prognostic markers. Subsequently it was prospectively validated in 1915 patients, accounted for the duration of MDS and prior therapy [49]. One should take note that the MDACC model should only be applied to the population of patients with lower-risk (low or intermediate-1 IPSS) MDS, and patients who received various of MDS treatment, from which it was derived [50].

The pathogenesis of MDS is considered as a multistep process involving sequential acquisition of oncogenic mutations [51, 52]. The interplay between genetically altered HSCs and an abnormal bone marrow microenvironment may allow for

MDS is driven by a multistep process characterized by recurrent mutations affecting basic cellular pathways, including RNA splicing, epigenome regulation, myeloid transcription coordination, DNA damage response and growth factor signaling. It has been long recognized that HSC with certain pathogenic alterations

*DOI: http://dx.doi.org/10.5772/intechopen.82166*

intermediate-2 risk, and 0.4 year for high risk.

be used at any time during the disease course.

selection of a predominant dysplastic clone [51–56].

**3.1 Clonal heterogeneity and evolution**

#### *Myelodysplastic Syndromes: An Update on Pathophysiology and Management DOI: http://dx.doi.org/10.5772/intechopen.82166*

*Recent Developments in Myelodysplastic Syndromes*

Chronic myelomonocytic leukemia(CMML)

Juvenile myelomonocytic leukemia (JMML)

*Provisional entity: Refractory cytopenia of childhood* Myeloid neoplasms with germline predisposition Acute myeloid leukemia (AML) and related neoplasms

Blastic plasmacytoid dendritic cell neoplasm Acute leukemias of ambiguous lineage B-lymphoblastic leukemia/lymphoma T-lymphoblastic leukemia/lymphoma

Myelodysplastic/myeloproliferative neoplasms (MDS/MPN)

MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)

Atypical chronic myeloid leukemia (aCML), BCR-ABL1

Myeloproliferative neoplasms

MDS/MPN, unclassifiable Myelodysplastic syndrome MDS with single lineage dysplasia MDS with ring sideroblasts (MDS-RS) MDS-RS and single lineage dysplasia MDS-RS and multilineage dysplasia MDS with multilineage dysplasia MDS with excess blasts MDS with isolated del(5q) MDS, unclassifiable

with PCM1-JAK2

with ring sideroblasts and multilineage dysplasia, marked thrombocytosis, lacking excess blasts or an isolated del(5q) abnormality is included into the category of MDS with ring sideroblasts, and correlates with a favorable prognosis [40–43].

*Classification of myeloid neoplasms and acute leukemia, according to World Health Organization 2016* 

Includes AML with myelodysplasia-related changes and therapy-related myeloid neoplasms

Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or

MDS must be distinguished from other marrow dysplasia secondary to reversible causes, such as folate and vitamin B12 deficiency, viral infections (e.g. HIV), antibiotics, benzene, ethanol, or lead poisoning. Other primary bone marrow disorders presenting as pancytopenia, such as aplastic anemia, paroxysmal nocturnal hematuria, hairy cell leukemia, large granular lymphocytic leukemia can be distinguished by marrow morphology, flow cytometry features and gene mutation profile [8].

The natural history of MDS in patients varies. The heterogeneity reflects both known and unknown differences in the pathophysiology of specific disease subtypes and patient related characteristics. Several prognostic scoring systems were developed and validated for MDS patients. In 1996, the International Prognostic Scoring System (IPSS) was developed by the International MDS Risk Analysis Workshop based on FAB classification [44]. Based on percent bone marrow blasts, specific cytogenetic abnormalities, and the number of cell lines involved with dysplasia and cytopenia, individual patient are placed into 4 groups: low,

**66**

**2.3 Differential diagnosis**

**Table 2.**

*criteria.*

**2.4 Risk stratification**

intermediate-1, intermediate-2, and high. The median survival in these four risk categories is 5.7 years for low risk, 3.5 years for intermediate-1 risk, 1.2 years for intermediate-2 risk, and 0.4 year for high risk.

In 2012, a revised IPSS (IPSS-R) was developed based upon data from 7012 patients with primary MDS diagnosed using the FAB or WHO classifications [45]. It incorporated new cytogenetic categories [35], and differentially weighed the degree of cytopenias in newly diagnosed patients. Patient age is an optional variable that can be incorporated to predict overall survival, but not evolution to AML. Individual patient was categorized into five risk groups: very low, low, intermediate, high and very high risk, that translates into median survival of 8.8, 5.3, 3.0, 1.6 and 0.8 years respectively. IPSS-R is simple to use, and is perhaps the most commonly used prognostication system today. However, there are several potential limitations to the IPSS-R. Both IPSS and IPSS-R were developed using data from patients who were observed without treatment. While outcomes might be different now that a variety of interventions are available, an analysis of a separate population suggested that the predictive value of the IPSS-R also applies to those treated with lenalidomide and azacitidine. [46] The prognosticating system only considered patients with *de novo* MDS. It is well recognized that patients with secondary MDS are more likely to have shorter survival. Much of this reflects the association between secondary MDS and "unfavorable cytogenetics". In addition, the IPSS-R seems to be most reliable at predicting outcomes at initial disease diagnosis, as the hazards in mortality and leukemia transformation diminishes over time in higherrisk but remains stable in lower-risk patients [47]. With increasing knowledge of MDS clonal genetics, the future risk stratification system might incorporate the prognostic value of mutation profile, which will be discussed in the next section.

WHO prognostic scoring system (WPSS) was designed to include information on red blood cell (RBC) transfusion need and cytogenetic information [48]. A subset of patients in the study cohort had data from multiple time points for a time-dependent analysis, therefore had the advantage over the IPSS of being able to be used at any time during the disease course.

The MD Anderson Cancer Center (MADCC) MDS model was developed based on a retrospective analysis of 856 patients with *de novo* or therapy-related MDS [49]. Age, cytogenetics, degree of anemia and thrombocytopenia, bone marrow blast percentage were identified as prognostic markers. Subsequently it was prospectively validated in 1915 patients, accounted for the duration of MDS and prior therapy [49]. One should take note that the MDACC model should only be applied to the population of patients with lower-risk (low or intermediate-1 IPSS) MDS, and patients who received various of MDS treatment, from which it was derived [50].

### **3. Pathogenesis**

The pathogenesis of MDS is considered as a multistep process involving sequential acquisition of oncogenic mutations [51, 52]. The interplay between genetically altered HSCs and an abnormal bone marrow microenvironment may allow for selection of a predominant dysplastic clone [51–56].

#### **3.1 Clonal heterogeneity and evolution**

MDS is driven by a multistep process characterized by recurrent mutations affecting basic cellular pathways, including RNA splicing, epigenome regulation, myeloid transcription coordination, DNA damage response and growth factor signaling. It has been long recognized that HSC with certain pathogenic alterations has a competitive advantage and drives clonal expansion at the stem cell level. Clonal cytogenetic abnormalities are detected in up to 50% of *de novo* MDS cases and 80% of therapy-related cases [57, 58]. Over the past decade, a number of large, MDS-focused sequencing studies further demonstrated that MDS is a genetically complex and heterogeneous disease [36, 37, 42, 59–61].

However, clonality alone is not sufficient to cause or diagnose disease, because increased clonal hematopoiesis can remain functionally intact [38, 39]. Recently published data on a large cohort of cytopenia (ICUS) patients delineated the natural history of patients with clonal vs. nonclonal cytopenia [62]. Patients with clonal ICUS had a much higher rate of progression than patient with nonclonal ICUS. Spliceosome gene mutations such as SF3B1 SRSF2 and U2AF1 and co-mutation patterns involving TET2, DNMT3A or ASXL1 had clinical characteristics resemble low-risk MDS patients, and higher progression to myeloid neoplasm when comparing with patient with somatic TET2, DNMT3A and ASXL1 mutation alone [39].

The diversity of clinical MDS phenotypes associated with specific mutations may be related to differential coregulation of the HSC self-renewal and lineagespecific differentiation capacity. Accurate prediction of the natural history of individual patient is certainly of high clinic interest. Our growing knowledge suggests that individual mutations occur in highly stereotyped order and strong patterns of co-mutation association and exclusivity (**Figure 1**) [36, 60, 63]. Mutations affecting epigenetic modifier genes (DNMT3A, TET2, ASXL1, EZH2, etc.) or RNA spliceosome components (SF3B1, SRSF2, and U2AF1) tend to arise in the initiation and early progression phase of MDS and rarely occur at the time of transformation. By contrast, mutations in growth factor signaling pathways (NRAS, KRAS, PTPN11, FLT3, etc.) are rarely found in early phase of disease, and instead, they are frequently acquired and expanded in subclones at time of progression to high-grade MDS or secondary AML [63–66]. A recent study [67] suggested that at the time of

#### **Figure 1.**

*Gene mutations have stereotyped positions in the MDS clonal hierarchy. Recent knowledge suggests that individual mutations occurs in highly stereotyped order and strong patterns of co-mutation association and exclusivity (Mutations affecting epigenetic modifier genes (DNMT3A, TET2, ASXL1, EZH2, etc.) or RNA spliceosome components (SF3B1, SRSF2, and U2AF1) tend to arise in the initiation and early progression phase of MDS and rarely occur at the time of transformation. Mutations in growth factor signaling pathways (NRAS, KRAS, PTPN11, FLT3, etc.) are frequently acquired and expanded in subclones at time of progression to high-grade MDS or secondary AML.*

**69**

**4. Treatment**

*Myelodysplastic Syndromes: An Update on Pathophysiology and Management*

gene alterations causes myeloproliferative disorders [79, 80].

secondary AML transformation, the founding clone persisted at high variant allele fraction, but there was selective emergence and dominance of at least one genetically distinct subclone. In t-MDS, mutations in PPM1D or TP53 were present in 46% of patients, and they were the only gene mutations that were significantly associ-

Various studies have also assessed the value of risk stratification based on MDS mutation profile [36, 42, 72]. TP53, ETV6, ASXL1, EZH2 and RUNX1 mutation confers adverse outcomes that are independent of IPSS risk assessment. SF3B1, which is frequently mutated in patients with ring sideroblasts, is associated with distinct and

HSC and genetically altered HSC all reside in a highly complex and dynamic cellular microenvironment in the bone marrow, that is composed of endothelial cells, multipotent mesenchymal stem cells, and sympathetic nerve fibers. There have been many *in vivo* studies demonstrated the concept of niche-induced disease initiation of MDS [73, 74] or AML [75, 76]. Evidence to support this in humans is mainly based on the not-so-rare occurrence of donor-derived leukemia in bone marrow transplant recipients, where changes in the preexisting niche in the host is thought to be leukemogenic [77]. In the review by Pleyer et al., [78] a variety of functional and molecular alterations were observed in *ex vivo* expanded mesenchymal stromal cells from MDS and AML patients, including their differentiation potential and HSC supportive activities, as well as chromosomal aberrations, transcriptional, and epigenetic changes. *In vivo* evidence also suggested that endothelial cells-specific

Regulators of inflammation and innate immunity have always been thought to play an important role in pathogenesis of malignancies, but only until recent have the specific immune effectors and their cell-intrinsic functional roles in MDS stem cell biology been elucidated [81, 82]. Therapeutic targeting of over-activated innate immune components such as Toll-like receptors [83], IL-1 receptor–associated kinase/tumor necrosis factor receptor–associated factor-6 [84], IL8/CXCR2 [85], and IL1RAP [86] signaling pathways in MDS HSCs is being attempted pre-clinically.

Treatment for MDS is guided by clinical symptoms, disease risk classification, patient age, comorbidities and performance status. Supportive care with transfusion and timely treatment of infection with antibiotics are important adjuncts for all MDS patients. Incorporating iron chelation therapy for patients requiring chronic transfusion and all candidates for allogeneic stem cell transplant is being increasingly emphasized to prevent cardiac and liver damage from iron overload [87, 88]. Pharmacologic treatment is usually reserved for symptomatic patients. Treatment goal for lower-risk MDS patients is to minimize symptoms, improve quality of life, and avoid toxicity from therapy. Erythropoiesis stimulating agent (ESA) can be used for symptomatic anemia and a low serum erythropoietin [89–92]. Together with low-dose G-CSF, hemoglobin improvement can be seen in up to 40% of lower-risk patients [93, 94]. Immunosuppressive therapy with antithymocyte globulin and cyclosporine A can produce response in a selected subset of

*DOI: http://dx.doi.org/10.5772/intechopen.82166*

ated with t-MDS [63, 68–71].

favorable clinical features [37, 38, 40].

**3.2 Bone marrow microenvironment**

**3.3 Dysregulated immune pathways**

*Myelodysplastic Syndromes: An Update on Pathophysiology and Management DOI: http://dx.doi.org/10.5772/intechopen.82166*

secondary AML transformation, the founding clone persisted at high variant allele fraction, but there was selective emergence and dominance of at least one genetically distinct subclone. In t-MDS, mutations in PPM1D or TP53 were present in 46% of patients, and they were the only gene mutations that were significantly associated with t-MDS [63, 68–71].

Various studies have also assessed the value of risk stratification based on MDS mutation profile [36, 42, 72]. TP53, ETV6, ASXL1, EZH2 and RUNX1 mutation confers adverse outcomes that are independent of IPSS risk assessment. SF3B1, which is frequently mutated in patients with ring sideroblasts, is associated with distinct and favorable clinical features [37, 38, 40].

#### **3.2 Bone marrow microenvironment**

*Recent Developments in Myelodysplastic Syndromes*

complex and heterogeneous disease [36, 37, 42, 59–61].

has a competitive advantage and drives clonal expansion at the stem cell level. Clonal cytogenetic abnormalities are detected in up to 50% of *de novo* MDS cases and 80% of therapy-related cases [57, 58]. Over the past decade, a number of large, MDS-focused sequencing studies further demonstrated that MDS is a genetically

However, clonality alone is not sufficient to cause or diagnose disease, because increased clonal hematopoiesis can remain functionally intact [38, 39]. Recently published data on a large cohort of cytopenia (ICUS) patients delineated the natural history of patients with clonal vs. nonclonal cytopenia [62]. Patients with clonal ICUS had a much higher rate of progression than patient with nonclonal ICUS. Spliceosome gene mutations such as SF3B1 SRSF2 and U2AF1 and co-mutation patterns involving TET2, DNMT3A or ASXL1 had clinical characteristics resemble low-risk MDS patients, and higher progression to myeloid neoplasm when comparing with patient with somatic TET2, DNMT3A and ASXL1 mutation alone [39]. The diversity of clinical MDS phenotypes associated with specific mutations may be related to differential coregulation of the HSC self-renewal and lineagespecific differentiation capacity. Accurate prediction of the natural history of individual patient is certainly of high clinic interest. Our growing knowledge suggests that individual mutations occur in highly stereotyped order and strong patterns of co-mutation association and exclusivity (**Figure 1**) [36, 60, 63]. Mutations affecting epigenetic modifier genes (DNMT3A, TET2, ASXL1, EZH2, etc.) or RNA spliceosome components (SF3B1, SRSF2, and U2AF1) tend to arise in the initiation and early progression phase of MDS and rarely occur at the time of transformation. By contrast, mutations in growth factor signaling pathways (NRAS, KRAS, PTPN11, FLT3, etc.) are rarely found in early phase of disease, and instead, they are frequently acquired and expanded in subclones at time of progression to high-grade MDS or secondary AML [63–66]. A recent study [67] suggested that at the time of

**68**

**Figure 1.**

*to high-grade MDS or secondary AML.*

*Gene mutations have stereotyped positions in the MDS clonal hierarchy. Recent knowledge suggests that individual mutations occurs in highly stereotyped order and strong patterns of co-mutation association and exclusivity (Mutations affecting epigenetic modifier genes (DNMT3A, TET2, ASXL1, EZH2, etc.) or RNA spliceosome components (SF3B1, SRSF2, and U2AF1) tend to arise in the initiation and early progression phase of MDS and rarely occur at the time of transformation. Mutations in growth factor signaling pathways (NRAS, KRAS, PTPN11, FLT3, etc.) are frequently acquired and expanded in subclones at time of progression* 

HSC and genetically altered HSC all reside in a highly complex and dynamic cellular microenvironment in the bone marrow, that is composed of endothelial cells, multipotent mesenchymal stem cells, and sympathetic nerve fibers. There have been many *in vivo* studies demonstrated the concept of niche-induced disease initiation of MDS [73, 74] or AML [75, 76]. Evidence to support this in humans is mainly based on the not-so-rare occurrence of donor-derived leukemia in bone marrow transplant recipients, where changes in the preexisting niche in the host is thought to be leukemogenic [77]. In the review by Pleyer et al., [78] a variety of functional and molecular alterations were observed in *ex vivo* expanded mesenchymal stromal cells from MDS and AML patients, including their differentiation potential and HSC supportive activities, as well as chromosomal aberrations, transcriptional, and epigenetic changes. *In vivo* evidence also suggested that endothelial cells-specific gene alterations causes myeloproliferative disorders [79, 80].

#### **3.3 Dysregulated immune pathways**

Regulators of inflammation and innate immunity have always been thought to play an important role in pathogenesis of malignancies, but only until recent have the specific immune effectors and their cell-intrinsic functional roles in MDS stem cell biology been elucidated [81, 82]. Therapeutic targeting of over-activated innate immune components such as Toll-like receptors [83], IL-1 receptor–associated kinase/tumor necrosis factor receptor–associated factor-6 [84], IL8/CXCR2 [85], and IL1RAP [86] signaling pathways in MDS HSCs is being attempted pre-clinically.

#### **4. Treatment**

Treatment for MDS is guided by clinical symptoms, disease risk classification, patient age, comorbidities and performance status. Supportive care with transfusion and timely treatment of infection with antibiotics are important adjuncts for all MDS patients. Incorporating iron chelation therapy for patients requiring chronic transfusion and all candidates for allogeneic stem cell transplant is being increasingly emphasized to prevent cardiac and liver damage from iron overload [87, 88]. Pharmacologic treatment is usually reserved for symptomatic patients. Treatment goal for lower-risk MDS patients is to minimize symptoms, improve quality of life, and avoid toxicity from therapy. Erythropoiesis stimulating agent (ESA) can be used for symptomatic anemia and a low serum erythropoietin [89–92]. Together with low-dose G-CSF, hemoglobin improvement can be seen in up to 40% of lower-risk patients [93, 94]. Immunosuppressive therapy with antithymocyte globulin and cyclosporine A can produce response in a selected subset of patients. Those most likely to benefit are younger than 60 years, with less than 5% bone marrow blasts, hypoplastic MDS, presence of a paroxysmal nocturnal hemoglobinuria clone, trisomy 8, human leukocyte antigen DR15 positive, and with short duration of transfusion dependence [95]. Low-dose lenalidomide at 10 mg daily is FDA-approved for lower-risk MDS characterized as the 5q- syndrome. Transfusion independence was achieved in 67% of patients in the phase 2 trial [96], and 56% in the phase 3 trial [97]. For ESA refractory lower-risk MDS patients without 5qsyndrome, lenalidomide in combination with ESA also demonstrated efficacy at reducing transfusion need [98–100]. So far, the only FDA approved therapies for higher-risk MDS are the HMAs azacitidine and decitabine. The use of these agents results in complete (CR) and partial response (PR) each in 10–20% patients, with median duration of response about 10 months [101–104]. An additional 20–30% patients achieve hematologic improvement without an objective response. Despite survival benefit demonstrated with azacitidine in high-risk patients [101], HMAs are not curative. For young and fit patients, allogeneic stem cell transplant is the only curative treatment option. Therefore, there remains a significant unmet therapeutic need beyond HMAs. Novel agents under clinical investigation and the use of allogeneic stem cell transplant will be discussed here.

#### **4.1 Next-generation hypomethylating agents**

HMAs are S-phase specific. Conventional HMAs all have a very short half-lives (less than 30 min) due to rapid clearance of azanucleoside by cytidine deaminase. The focus of newer generation HMA development has been to meet the need of prolonged drug exposure, allowing greater drug incorporation into DNA.

Oral film-coated azacitidine (CC-486) was first studied in an open-label pilot trial. It demonstrated 17% mean bioavailability after a single dose at 80 mg [105]. In a subsequent phase 1 dose finding study in MDS, CMML and AML patients, overall response rate was 73% in previously untreated patients, and 35% in previously treated patients [106]. Extended dosing schedule of CC-486 for 14 or 21 days is being evaluated in a phase 3 trial (NCT01566695) in lower-risk MDS [107]. CC-486 is also being studied in combination with immune check point inhibitor in the second line setting (NCT02281084).

ASTX727 is a novel formulation of oral decitabine paired with an oral cytidine deaminase inhibitor E7727 to overcome the rapid clearance from cytidine deaminase in gut and liver. In the early phase studies with intermediate- or high-risk MDS, ASTX727 (35 mg decitabine, 100 mg E7227) successfully emulated the pharmacokinetic profile of intravenous decitabine [108, 109]. In the phase 2 trial, clinical benefit was observed in 62% patients, with 16% CR, 28% marrow complete response (mCR), and 18% hematologic improvement [109].

Another strategy to circumvent the rapid degradation of azanucleotide is to develop a novel formulation that is relatively resistant to cytidine deamination. Guadecitabine (SGI-110) is a novel dinucleotide of decitabine and deoxyguanosine, linked by a phosphodiester bond, that leads to a slower release of the active decitabine moiety, prolonging cellular exposure to the drug [110]. In the phase 2 study with guadecitabine in intermediate and high risk MDS and CMML patients, CR was observed in 7/49 treatment naïve patients (14%) while CR + mCR were observed in 11/53 previously treated patients (21%) [111].

#### **4.2 Histone deacetylase inhibition**

Both DNA-promoter hypomethylation as well as post-translational modification of histone tails (e.g., deacetylation) lead to transcriptional silencing of tumor-suppressor

**71**

*Myelodysplastic Syndromes: An Update on Pathophysiology and Management*

genes and genes involved in differentiation and apoptosis [112, 113]. Histone deacetylase inhibitors (HDACi) have limited single-agent efficacy in both high risk MDS and AML [114–116]. Preclinical evidence supported synergy between HMAs and HDACi [117]. However, a few phase 2 randomized clinical trials failed to demonstrate improvement in response rates or survival when azacitidine was combined with HDACi entinostat, vorinostat, valproic acid, or pracinostat [118–122]. Currently, a few clinical trials in MDS are ongoing using HDACi in combination with other novel agents such as immune checkpoint inhibitors (NCT 02936752) or pracinostat in combination with azacitidine using different dosing scheme (NCT 03151304). At this moment, how to best incorporate HDACi in MDS treatment remains uncertain.

Beyond targeting DNA methylation and HDAC recruitment, there has also been an increasing effort to develop epigenetic modification agents targeting posttranslation or posttranscription pathways, to mitigate malignant myeloid transformation in MDS. Bromodomain and extraterminal (BET) proteins are epigenetic readers that recognize acetylated lysine tails of histones, and thus areas of open chromatin structure. It has been suggested that AML relies on BET protein BRD4 [123, 124], therefore led to great interest in utilizing BET inhibitors in myeloid malignancy. Various clinical trials are investigating the use of JQ1, the first selective BET inhibitor, in myeloid malignancy including MDS (NCT 02158858, NCT 02308761).

Overexpression of the mono and dimethyl lysine demethylase, LSD1 has been implicated in myeloid malignancies [125]. Clinical trials are ongoing evaluating LSD1 inhibitors in combination with ATRA or HMA in previously treated AML and

Upregulation of immune checkpoint molecules like PD-1/PDL-1 and CTLA4 is commonly observed in many malignancies, including AML and MDS [126, 127] to evade immune surveillance. However, preliminary experience suggested limited activity of immune checkpoint inhibitor use as single agent after HMA failure in MDS patients [128]. Several clinical trials are ongoing evaluating the efficacy of immune checkpoint inhibitors plus HMAs or HDACis (NCT02530463, NCT03092674,

Based on the mutation profile, FLT3 inhibitor and IDH1/2 inhibitors are now FDA approved for AML. However, these mutations are less common in MDS [129]. The early phase ½ studies of IDH1 and IDH2 inhibitors included MDS patients, with reported response [130, 131]. Especially given their tolerability profile and

Spliceosome mutations, such as SF3B1, SRSF2 and U2AF1 are the most common mutations in MDS [37]. Based on the encouraging activity in preclinical study [132], there is now a phase 1 study in myeloid malignancies including MDS, with splicing modulator H3B-8800, an oral modulator of the SF3B complex (NCT02841540). Venetoclax, a selective BCL-2 inhibitor was granted breakthrough designation by FDA in combination with decitabine in 2017 for treatment–naive AML patients age greater than 65 years. This decision was based on result from two ongoing phase ½ clinical trials [133]. This combination is now being evaluated in higher-risk MDS

MDS patients (NCT02273102, NCT02717884, NCT02929498).

**4.5 Other targeted therapies: extrapolating experience from AML**

single agent activity, these agents deserves further investigation in MDS.

in both frontline and HMA failure settings (NCT02966782, NCT02942290).

*DOI: http://dx.doi.org/10.5772/intechopen.82166*

**4.3 Other epigenetic modification agents**

**4.4 Immune checkpoint inhibition**

NCT02775903, NCT03094637, NCT02599649).

*Myelodysplastic Syndromes: An Update on Pathophysiology and Management DOI: http://dx.doi.org/10.5772/intechopen.82166*

genes and genes involved in differentiation and apoptosis [112, 113]. Histone deacetylase inhibitors (HDACi) have limited single-agent efficacy in both high risk MDS and AML [114–116]. Preclinical evidence supported synergy between HMAs and HDACi [117]. However, a few phase 2 randomized clinical trials failed to demonstrate improvement in response rates or survival when azacitidine was combined with HDACi entinostat, vorinostat, valproic acid, or pracinostat [118–122]. Currently, a few clinical trials in MDS are ongoing using HDACi in combination with other novel agents such as immune checkpoint inhibitors (NCT 02936752) or pracinostat in combination with azacitidine using different dosing scheme (NCT 03151304). At this moment, how to best incorporate HDACi in MDS treatment remains uncertain.

#### **4.3 Other epigenetic modification agents**

*Recent Developments in Myelodysplastic Syndromes*

allogeneic stem cell transplant will be discussed here.

**4.1 Next-generation hypomethylating agents**

second line setting (NCT02281084).

**4.2 Histone deacetylase inhibition**

response (mCR), and 18% hematologic improvement [109].

observed in 11/53 previously treated patients (21%) [111].

patients. Those most likely to benefit are younger than 60 years, with less than 5% bone marrow blasts, hypoplastic MDS, presence of a paroxysmal nocturnal hemoglobinuria clone, trisomy 8, human leukocyte antigen DR15 positive, and with short duration of transfusion dependence [95]. Low-dose lenalidomide at 10 mg daily is FDA-approved for lower-risk MDS characterized as the 5q- syndrome. Transfusion independence was achieved in 67% of patients in the phase 2 trial [96], and 56% in the phase 3 trial [97]. For ESA refractory lower-risk MDS patients without 5qsyndrome, lenalidomide in combination with ESA also demonstrated efficacy at reducing transfusion need [98–100]. So far, the only FDA approved therapies for higher-risk MDS are the HMAs azacitidine and decitabine. The use of these agents results in complete (CR) and partial response (PR) each in 10–20% patients, with median duration of response about 10 months [101–104]. An additional 20–30% patients achieve hematologic improvement without an objective response. Despite survival benefit demonstrated with azacitidine in high-risk patients [101], HMAs are not curative. For young and fit patients, allogeneic stem cell transplant is the only curative treatment option. Therefore, there remains a significant unmet therapeutic need beyond HMAs. Novel agents under clinical investigation and the use of

HMAs are S-phase specific. Conventional HMAs all have a very short half-lives (less than 30 min) due to rapid clearance of azanucleoside by cytidine deaminase. The focus of newer generation HMA development has been to meet the need of prolonged drug exposure, allowing greater drug incorporation into DNA.

Oral film-coated azacitidine (CC-486) was first studied in an open-label pilot trial. It demonstrated 17% mean bioavailability after a single dose at 80 mg [105]. In a subsequent phase 1 dose finding study in MDS, CMML and AML patients, overall response rate was 73% in previously untreated patients, and 35% in previously treated patients [106]. Extended dosing schedule of CC-486 for 14 or 21 days is being evaluated in a phase 3 trial (NCT01566695) in lower-risk MDS [107]. CC-486 is also being studied in combination with immune check point inhibitor in the

ASTX727 is a novel formulation of oral decitabine paired with an oral cytidine deaminase inhibitor E7727 to overcome the rapid clearance from cytidine deaminase in gut and liver. In the early phase studies with intermediate- or high-risk MDS, ASTX727 (35 mg decitabine, 100 mg E7227) successfully emulated the pharmacokinetic profile of intravenous decitabine [108, 109]. In the phase 2 trial, clinical benefit was observed in 62% patients, with 16% CR, 28% marrow complete

Another strategy to circumvent the rapid degradation of azanucleotide is to develop a novel formulation that is relatively resistant to cytidine deamination. Guadecitabine (SGI-110) is a novel dinucleotide of decitabine and deoxyguanosine, linked by a phosphodiester bond, that leads to a slower release of the active decitabine moiety, prolonging cellular exposure to the drug [110]. In the phase 2 study with guadecitabine in intermediate and high risk MDS and CMML patients, CR was observed in 7/49 treatment naïve patients (14%) while CR + mCR were

Both DNA-promoter hypomethylation as well as post-translational modification of histone tails (e.g., deacetylation) lead to transcriptional silencing of tumor-suppressor

**70**

Beyond targeting DNA methylation and HDAC recruitment, there has also been an increasing effort to develop epigenetic modification agents targeting posttranslation or posttranscription pathways, to mitigate malignant myeloid transformation in MDS.

Bromodomain and extraterminal (BET) proteins are epigenetic readers that recognize acetylated lysine tails of histones, and thus areas of open chromatin structure. It has been suggested that AML relies on BET protein BRD4 [123, 124], therefore led to great interest in utilizing BET inhibitors in myeloid malignancy. Various clinical trials are investigating the use of JQ1, the first selective BET inhibitor, in myeloid malignancy including MDS (NCT 02158858, NCT 02308761).

Overexpression of the mono and dimethyl lysine demethylase, LSD1 has been implicated in myeloid malignancies [125]. Clinical trials are ongoing evaluating LSD1 inhibitors in combination with ATRA or HMA in previously treated AML and MDS patients (NCT02273102, NCT02717884, NCT02929498).

#### **4.4 Immune checkpoint inhibition**

Upregulation of immune checkpoint molecules like PD-1/PDL-1 and CTLA4 is commonly observed in many malignancies, including AML and MDS [126, 127] to evade immune surveillance. However, preliminary experience suggested limited activity of immune checkpoint inhibitor use as single agent after HMA failure in MDS patients [128]. Several clinical trials are ongoing evaluating the efficacy of immune checkpoint inhibitors plus HMAs or HDACis (NCT02530463, NCT03092674, NCT02775903, NCT03094637, NCT02599649).

#### **4.5 Other targeted therapies: extrapolating experience from AML**

Based on the mutation profile, FLT3 inhibitor and IDH1/2 inhibitors are now FDA approved for AML. However, these mutations are less common in MDS [129]. The early phase ½ studies of IDH1 and IDH2 inhibitors included MDS patients, with reported response [130, 131]. Especially given their tolerability profile and single agent activity, these agents deserves further investigation in MDS.

Spliceosome mutations, such as SF3B1, SRSF2 and U2AF1 are the most common mutations in MDS [37]. Based on the encouraging activity in preclinical study [132], there is now a phase 1 study in myeloid malignancies including MDS, with splicing modulator H3B-8800, an oral modulator of the SF3B complex (NCT02841540).

Venetoclax, a selective BCL-2 inhibitor was granted breakthrough designation by FDA in combination with decitabine in 2017 for treatment–naive AML patients age greater than 65 years. This decision was based on result from two ongoing phase ½ clinical trials [133]. This combination is now being evaluated in higher-risk MDS in both frontline and HMA failure settings (NCT02966782, NCT02942290).

#### **4.6 Management of anemia in lower-risk MDS**

Luspatercept and sotatercept are modified activin receptor type II (ActRII) chimeric fusion proteins that consist of the modified extracellular domain of ActRIIB and ActRIIA respectively, trap TGF-β superfamily ligands to promote late-stage erythropoiesis [134, 135]. In the phase 2 trial of luspatercept for patients with lower-risk MDS who were ineligible for or refractory to ESAs, RBC transfusion independence was seen in 38% patients, and 63% hematologic improvement [136]. Similar efficacy was seen in the phase 2 trial for sotatercept, with 47% hematologic response in patients with high transfusion burden, and 58% with low transfusion burden [137]. Ongoing phase 3 clinical trial is evaluating the efficacy of ActRII antagonist in lower-risk MDS and MDS with ring sideroblasts who require regular RBC transfusions (NCT 02631070).

Rigosertib is a PI3K and polo-like kinase pathways small-molecule inhibitor. In the recent phase 2 study for transfusion-dependent lower-risk MDS patients, 20 of 62 (32%) patients achieved transfusion independence lasting for more than 8 weeks [138]. Validation of these results in future clinical trials is anticipated.

Roxadustat is a drug which acts as a HIF prolyl-hydroxylase inhibitor and thereby increases endogenous production of erythropoietin, which stimulates production of hemoglobin and RBCs. Roxadustat is shown to be safe and effective as anemia treatment for patient with underlying chronic kidney disease, not on dialysis [139]. A phase 3 trial is ongoing to evaluate the efficacy of roxadustat in low-risk MDS patients with low transfusion burden (NCT03263091).

#### **4.7 Allogeneic stem cell transplant**

Allogeneic stem cell transplant is the only curative therapy for MDS, but restricted to younger and fit patients. Disease free survival rates are approximately 30–50%. Treatment failure is attributed by transplant-related mortality in low-risk patients, and relapse in higher-risk patients [140]. In general, bone marrow transplant is offered to intermediate-2 and high-risk MDS patients. Over the past decade, reduced-intensity conditioning transplant made more older patients eligible for transplant [141]. An ongoing clinical trial is comparing the efficacy of reduced intensity allogeneic stem cell transplant to HMA in patients aged 50–75 with higher-risk disease [142]. In the study by Della Porta et al. [143], IPSS-R was prognostic for outcomes of patients in the high and very high-risk groups, but not in the low- and intermediate-risk groups.

There have been emerging data on the prognostic value of mutation profile and minimal residual disease pre- and post-transplantation. It was shown that only a minority of patients with MDS was in deep hematologic remission by flow cytometry minimal residual disease (MRD) and cytogenetic analysis before transplant [144]. For myeloablative conditioning, MRD positive and MRD negative patients had similar post-transplant outcome. However, relapse rate was higher for MRD positive patient who received non-myeloablative conditioning. Multiple studies have shown that TP53 mutation is an independent marker for short survival posttransplant [59, 61, 145]. EZH2, ETV6, RUNX1, ASXL1, JAK2, and mutations in the RAS signaling pathway have all been implicated to associate with short relapse-free interval post-transplant [59, 61, 145, 146].

#### **5. Conclusion**

Over the past decade, knowledge was gained in understanding the pathogenesis of MDS. However, many gaps remain to change the natural history of MDS. With

**73**

**Author details**

provided the original work is properly cited.

Wanxing Chai-Ho and Gary J. Schiller\*

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

UCLA Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

\*Address all correspondence to: gschiller@mednet.ucla.edu

*Myelodysplastic Syndromes: An Update on Pathophysiology and Management*

Wanxing Chai-Ho reports no conflict-of-interest.

getting closer to more therapeutics options for MDS in the near future.

Genetics, Spectrum, Stanford University Health, Sunesis, and Takeda.

increasing number of novel treatments under investigation, it is likely that we are

Gary Schiller receives research funding from Forma, Janssen, Onconova, Pfizer, Incyte and BioMed Valley Discoveries, and receives consulting fees from Agios, Amgen, Astellas, Bioline RX, Celgene, Gamida, Fanssen, Karyopharm, Leukemia Lymphoma Society, Medallion, Medeor, Merck, Pharmacyclics, Sanofi, Seattle

*DOI: http://dx.doi.org/10.5772/intechopen.82166*

**Conflict of interest**

increasing number of novel treatments under investigation, it is likely that we are getting closer to more therapeutics options for MDS in the near future.

## **Conflict of interest**

*Recent Developments in Myelodysplastic Syndromes*

RBC transfusions (NCT 02631070).

**4.7 Allogeneic stem cell transplant**

interval post-transplant [59, 61, 145, 146].

**4.6 Management of anemia in lower-risk MDS**

Luspatercept and sotatercept are modified activin receptor type II (ActRII) chimeric fusion proteins that consist of the modified extracellular domain of ActRIIB and ActRIIA respectively, trap TGF-β superfamily ligands to promote late-stage erythropoiesis [134, 135]. In the phase 2 trial of luspatercept for patients with lower-risk MDS who were ineligible for or refractory to ESAs, RBC transfusion independence was seen in 38% patients, and 63% hematologic improvement [136]. Similar efficacy was seen in the phase 2 trial for sotatercept, with 47% hematologic response in patients with high transfusion burden, and 58% with low transfusion burden [137]. Ongoing phase 3 clinical trial is evaluating the efficacy of ActRII antagonist in lower-risk MDS and MDS with ring sideroblasts who require regular

Rigosertib is a PI3K and polo-like kinase pathways small-molecule inhibitor. In the recent phase 2 study for transfusion-dependent lower-risk MDS patients, 20 of 62 (32%) patients achieved transfusion independence lasting for more than 8 weeks

Allogeneic stem cell transplant is the only curative therapy for MDS, but restricted to younger and fit patients. Disease free survival rates are approximately 30–50%. Treatment failure is attributed by transplant-related mortality in low-risk patients, and relapse in higher-risk patients [140]. In general, bone marrow transplant is offered to intermediate-2 and high-risk MDS patients. Over the past decade, reduced-intensity

conditioning transplant made more older patients eligible for transplant [141].

An ongoing clinical trial is comparing the efficacy of reduced intensity allogeneic stem cell transplant to HMA in patients aged 50–75 with higher-risk disease [142]. In the study by Della Porta et al. [143], IPSS-R was prognostic for outcomes of patients in the high and very high-risk groups, but not in the low- and intermediate-risk groups.

There have been emerging data on the prognostic value of mutation profile and minimal residual disease pre- and post-transplantation. It was shown that only a minority of patients with MDS was in deep hematologic remission by flow cytometry minimal residual disease (MRD) and cytogenetic analysis before transplant [144]. For myeloablative conditioning, MRD positive and MRD negative patients had similar post-transplant outcome. However, relapse rate was higher for MRD positive patient who received non-myeloablative conditioning. Multiple studies have shown that TP53 mutation is an independent marker for short survival posttransplant [59, 61, 145]. EZH2, ETV6, RUNX1, ASXL1, JAK2, and mutations in the RAS signaling pathway have all been implicated to associate with short relapse-free

Over the past decade, knowledge was gained in understanding the pathogenesis of MDS. However, many gaps remain to change the natural history of MDS. With

Roxadustat is a drug which acts as a HIF prolyl-hydroxylase inhibitor and thereby increases endogenous production of erythropoietin, which stimulates production of hemoglobin and RBCs. Roxadustat is shown to be safe and effective as anemia treatment for patient with underlying chronic kidney disease, not on dialysis [139]. A phase 3 trial is ongoing to evaluate the efficacy of roxadustat in

[138]. Validation of these results in future clinical trials is anticipated.

low-risk MDS patients with low transfusion burden (NCT03263091).

**72**

**5. Conclusion**

Wanxing Chai-Ho reports no conflict-of-interest.

Gary Schiller receives research funding from Forma, Janssen, Onconova, Pfizer, Incyte and BioMed Valley Discoveries, and receives consulting fees from Agios, Amgen, Astellas, Bioline RX, Celgene, Gamida, Fanssen, Karyopharm, Leukemia Lymphoma Society, Medallion, Medeor, Merck, Pharmacyclics, Sanofi, Seattle Genetics, Spectrum, Stanford University Health, Sunesis, and Takeda.

## **Author details**

Wanxing Chai-Ho and Gary J. Schiller\* UCLA Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

\*Address all correspondence to: gschiller@mednet.ucla.edu

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Diego, CA. Blood. 2015;**126**:327

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[135] Dussiot M, Maciel TT, Fricot A, et al. An activin receptor IIA ligand trap corrects ineffective erythropoiesis in β-thalassemia. Nature Medicine. 2014;**20**(4):398-407. DOI: 10.1038/

[136] Platzbecker U, Germing U, Götze KS, et al. Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): A multicentre, openlabel phase 2 dose-finding study with long-term extension study. The Lancet Oncology. 2017;**18**(10):1338-1347. DOI: 10.1016/S1470-2045(17)30615-0

[137] Komrokji R, Garcia-Manero G, Ades L, et al. Sotatercept with longterm extension for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes: A phase 2, dose-ranging trial. The Lancet Haematology. 2018;**5**(2):e63-e72. DOI: 10.1016/S2352-3026(18)30002-4

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*Myelodysplastic Syndromes: An Update on Pathophysiology and Management DOI: http://dx.doi.org/10.5772/intechopen.82166*

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[122] Garcia-Manero G, Montalban-Bravo G, Berdeja JG, et al. Phase 2, randomized, double-blind study of pracinostat in combination with azacitidine in patients with untreated, higher-risk myelodysplastic syndromes. Cancer. 2017;**123**(6):994-1002. DOI:

[123] Dawson MA, Prinjha RK, Dittmann A, et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature. 2011;**478**(7370):529-533. DOI: 10.1038/

[124] Zuber J, Shi J, Wang E, et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature. 2011;**478**(7370):524-528. DOI:

[125] Schenk T, Chen WC, Göllner S, et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-transretinoic acid differentiation pathway in acute myeloid leukemia. Nature Medicine. 2012;**18**(4):605-611. DOI:

[126] Zhang L, Gajewski TF, Kline J. PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model.

cncr.29085

10.1002/cncr.30533

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[128] Garcia-Manero G, Daver N, Montalban-Bravo G, et al. A phase II study evaluating the combination of nivolumab (Nivo) or ipilimumab (Ipi) with azacitidine in pts with previously treated or untreated myelodysplastic syndromes (MDS). In the 58th american Society of Hematology annual meeting and exposition, 3-6 December 2016, San Diego, CA. Blood. 2016;**128**(22):344

[129] DiNardo CD, Jabbour E, Ravandi F, et al. IDH1 and IDH2 mutations in myelodysplastic syndromes and role in disease progression. Leukemia. 2016;**30**(4):980-984. DOI: 10.1038/ leu.2015.211

[130] Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;**130**(6):722-731. DOI: 10.1182/ blood-2017-04-779405

[131] CD DN, de Botton S, Stein EM, et al. Determination of IDH1 mutational burden and clearance via nextgeneration sequencing in patients with IDH1 mutation-positive hematologic malignancies receiving AG-120, a firstin-class inhibitor of mutant IDH1. In the 58th american Society of Hematology annual meeting and exposition, 3-6 December 2016, San Diego, CA. Blood. 2016;**128**(22):1070

[132] Buonamici SY, Yoshimi A, Thomas M, et al. H3B-8800, an orally bioavailable modulator of the SF3b complex, shows efficacy in spliceosomemutant myeloid malignancies. In the

58th American Society of Hematology annual meeting and exposition, 3-6 December 2016, San Diego, CA. Blood. 2016;**128**(22):966

[133] DiNardo C, Pollyea DA, Pratz K, et al. A phase 1b study of venetoclax (ABT-199/GDC-0199) in combination with decitabine or azacitidine in treatment-naive patients with acute myelogenous leukemia who are ≥ to 65 years and not eligible for standard induction therapy. In the 58th American Society of Hematology annual meeting and exposition, 3-6 December 2016, San Diego, CA. Blood. 2015;**126**:327

[134] Suragani RN, Cadena SM, Cawley SM, et al. Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting latestage erythropoiesis. Nature Medicine. 2014;**20**(4):408-414. DOI: 10.1038/ nm.3512

[135] Dussiot M, Maciel TT, Fricot A, et al. An activin receptor IIA ligand trap corrects ineffective erythropoiesis in β-thalassemia. Nature Medicine. 2014;**20**(4):398-407. DOI: 10.1038/ nm.3468

[136] Platzbecker U, Germing U, Götze KS, et al. Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): A multicentre, openlabel phase 2 dose-finding study with long-term extension study. The Lancet Oncology. 2017;**18**(10):1338-1347. DOI: 10.1016/S1470-2045(17)30615-0

[137] Komrokji R, Garcia-Manero G, Ades L, et al. Sotatercept with longterm extension for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes: A phase 2, dose-ranging trial. The Lancet Haematology. 2018;**5**(2):e63-e72. DOI: 10.1016/S2352-3026(18)30002-4

[138] Azra R, Al-Kali A, Tibes R, et al. Rigosertib oral in transfusion dependent lower risk myelodysplastic syndromes (LR-MDS): Optimization of dose and rate of transfusion Independence (TI) or transfusion reduction (TR) in a single-arm phase 2 study. In the 59th American Society of Hematology annual meeting and exposition, 9-12 December 2017, Atlanta, GA. Blood. 2017;**130**:1689

[139] Besarab A, Provenzano R, Hertel J, et al. Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients. Nephrology, Dialysis, Transplantation. 2015;**30**(10):1665-1673. DOI: 10.1093/ndt/gfv302

[140] Sierra J, Perez WS, Rozman C, et al. Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia. Blood. 2002;**100**(6):1997-2004

[141] Alyea EP, Kim HT, Ho V, et al. Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age. Blood. 2005;**105**:1810-1814. DOI: 10.1182/blood-2004-05-1947

[142] Saber W, Le Rademacher J, Sekeres M, et al. Multicenter biologic assignment trial comparing reducedintensity allogeneic hematopoietic cell transplant to hypomethylating therapy or best supportive care in patients aged 50 to 75 with intermediate-2 and high-risk myelodysplastic syndrome: Blood and marrow transplant clinical trials network #1102 study rationale, design, and methods. Biology of Blood and Marrow Transplantation. 2014;**20**(10):1566-1572. DOI: 10.1016/j. bbmt.2014.06.010

[143] Della Porta MG, Alessandrino EP, Bacigalupo A, et al. Predictive factors for the outcome of allogeneic transplantation in patients with MDS stratified according to the revised

IPSS-R. Blood. 2014;**123**(15):2333-2342. DOI: 10.1182/blood-2013-12-542720

Chapter 6

Abstract

tics and prognosis.

1. Introduction

MDS [1].

85

noncoding RNAs, pathogenesis

Noncoding RNAs in

Myelodysplastic Syndromes

Andrea Hruštincová, Katarina Szikszai, Zdeněk Krejčík,

The discovery of short regulatory RNAs has recently directed the attention of scientists to parts of the genome that previously had been regarded as "junk" DNA because they did not encode protein products. The revelation that even proteinnoncoding sequences had biological functions began the era of discovering the world of noncoding RNAs (ncRNAs). Of these ncRNAs, microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are the most numerous and best-known ncRNA groups. miRNAs and lncRNAs are important regulators of hematopoiesis, and their abnormal function has serious implications for phenotypes. Deregulation of these ncRNAs is found in hematopoietic disorders, and they also contribute to the development and progression of myelodysplastic syndromes (MDS). Properties of ncRNAs such as stability and tissue specificity make these molecules highly promising diagnostic and prognostic markers as well as interesting therapeutic targets. This chapter summarizes our knowledge on the contribution of ncRNAs to the pathogenesis of MDS and discusses their potential applicability in disease diagnos-

Keywords: myelodysplastic syndromes, noncoding RNAs, microRNAs, long

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell (HSC) disorders, characterized by dysplastic and ineffective blood cell production, with a tendency for transformation to acute myeloid leukemia (AML). The diagnosis is generally suspected based on the presence of an abnormal complete blood count and is confirmed by performing bone marrow (BM) aspiration and biopsy, demonstrating morphological evidence of dysplasia. A number of additional tests, including cytogenetics, flow cytometry, and molecular genetics, are needed to complete the laboratory evaluation of patients with

Because of the large heterogeneity of MDS, the development of additional molecular tools able to refine the prognostic scoring system, to predict outcome, and to monitor the response to treatment is required. Recently, application of new high-throughput methods such as next-generation sequencing (NGS) has identified recurrent somatic mutations in MDS cells. In particular, point mutations in the TP53, EZH2, ETV6, RUNX1, and ASXL1 genes have been shown to be associated

Nikoleta Loudová and Michaela Dostálová Merkerová

[144] Festuccia M, Deeg HJ, Gooley TA, et al. Minimal identifiable disease and the role of conditioning intensity in hematopoietic cell transplantation for MDS and AML evolving from MDS. Biology of Blood and Marrow Transplantation. 2016;**22**(7):1227-1233. DOI: 10.1016/j.bbmt.2016.03.029

[145] Bejar R, Stevenson KE, Caughey B, et al. Somatic mutations predict poor outcome in patients with myelodysplastic syndrome after hematopoietic stem-cell transplantation. Journal of Clinical Oncology. 2014;**32**(25):2691-2698. DOI: 10.1200/JCO.2013.52.3381

[146] Bejar R, Stevenson K, Abdel-Wahab O, et al. Clinical effect of point mutations in myelodysplastic syndromes. The New England Journal of Medicine. 2011;**364**(26):2496-2506. DOI: 10.1056/NEJMoa1013343

## Chapter 6

*Recent Developments in Myelodysplastic Syndromes*

IPSS-R. Blood. 2014;**123**(15):2333-2342. DOI: 10.1182/blood-2013-12-542720

[144] Festuccia M, Deeg HJ, Gooley TA, et al. Minimal identifiable disease and the role of conditioning intensity in hematopoietic cell transplantation for MDS and AML evolving from MDS. Biology of Blood and Marrow Transplantation. 2016;**22**(7):1227-1233. DOI: 10.1016/j.bbmt.2016.03.029

[145] Bejar R, Stevenson KE,

10.1200/JCO.2013.52.3381

[146] Bejar R, Stevenson K, Abdel-Wahab O, et al. Clinical effect of point mutations in myelodysplastic syndromes. The New England Journal of Medicine. 2011;**364**(26):2496-2506.

DOI: 10.1056/NEJMoa1013343

Caughey B, et al. Somatic mutations predict poor outcome in patients with myelodysplastic syndrome after hematopoietic stem-cell transplantation. Journal of Clinical Oncology. 2014;**32**(25):2691-2698. DOI:

lower risk myelodysplastic syndromes (LR-MDS): Optimization of dose and rate of transfusion Independence (TI) or transfusion reduction (TR) in a single-arm phase 2 study. In the 59th American Society of Hematology annual meeting and exposition, 9-12 December 2017, Atlanta, GA. Blood. 2017;**130**:1689

[139] Besarab A, Provenzano R, Hertel J, et al. Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients. Nephrology, Dialysis,

Transplantation. 2015;**30**(10):1665-1673.

[140] Sierra J, Perez WS, Rozman C, et al. Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia. Blood.

DOI: 10.1093/ndt/gfv302

2002;**100**(6):1997-2004

[141] Alyea EP, Kim HT, Ho V, et al. Comparative outcome of nonmyeloablative and myeloablative

allogeneic hematopoietic cell

[142] Saber W, Le Rademacher J, Sekeres M, et al. Multicenter biologic assignment trial comparing reducedintensity allogeneic hematopoietic cell transplant to hypomethylating therapy or best supportive care in patients aged 50 to 75 with intermediate-2 and high-risk myelodysplastic syndrome: Blood and marrow transplant clinical trials network #1102 study rationale, design, and methods. Biology of Blood and Marrow Transplantation. 2014;**20**(10):1566-1572. DOI: 10.1016/j.

transplantation for patients older than 50 years of age. Blood. 2005;**105**:1810-1814. DOI: 10.1182/blood-2004-05-1947

**84**

bbmt.2014.06.010

[143] Della Porta MG, Alessandrino EP,

Bacigalupo A, et al. Predictive factors for the outcome of allogeneic transplantation in patients with MDS stratified according to the revised

## Noncoding RNAs in Myelodysplastic Syndromes

Andrea Hruštincová, Katarina Szikszai, Zdeněk Krejčík, Nikoleta Loudová and Michaela Dostálová Merkerová

#### Abstract

The discovery of short regulatory RNAs has recently directed the attention of scientists to parts of the genome that previously had been regarded as "junk" DNA because they did not encode protein products. The revelation that even proteinnoncoding sequences had biological functions began the era of discovering the world of noncoding RNAs (ncRNAs). Of these ncRNAs, microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are the most numerous and best-known ncRNA groups. miRNAs and lncRNAs are important regulators of hematopoiesis, and their abnormal function has serious implications for phenotypes. Deregulation of these ncRNAs is found in hematopoietic disorders, and they also contribute to the development and progression of myelodysplastic syndromes (MDS). Properties of ncRNAs such as stability and tissue specificity make these molecules highly promising diagnostic and prognostic markers as well as interesting therapeutic targets. This chapter summarizes our knowledge on the contribution of ncRNAs to the pathogenesis of MDS and discusses their potential applicability in disease diagnostics and prognosis.

Keywords: myelodysplastic syndromes, noncoding RNAs, microRNAs, long noncoding RNAs, pathogenesis

#### 1. Introduction

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell (HSC) disorders, characterized by dysplastic and ineffective blood cell production, with a tendency for transformation to acute myeloid leukemia (AML). The diagnosis is generally suspected based on the presence of an abnormal complete blood count and is confirmed by performing bone marrow (BM) aspiration and biopsy, demonstrating morphological evidence of dysplasia. A number of additional tests, including cytogenetics, flow cytometry, and molecular genetics, are needed to complete the laboratory evaluation of patients with MDS [1].

Because of the large heterogeneity of MDS, the development of additional molecular tools able to refine the prognostic scoring system, to predict outcome, and to monitor the response to treatment is required. Recently, application of new high-throughput methods such as next-generation sequencing (NGS) has identified recurrent somatic mutations in MDS cells. In particular, point mutations in the TP53, EZH2, ETV6, RUNX1, and ASXL1 genes have been shown to be associated

with specific clinical features and poor overall survival, independent of established risk factors [2]. Even though approximately 78% of MDS patients carry at least one oncogenic mutation [3], there is a long list of mutations in more than 50 genes with often unclear etiology, complicating the use of somatic mutations as simple and universal markers of MDS prognosis.

Concerning MDS pathogenesis, substantial progress has been made in recent years. A vast literature has become available regarding the spectrum of cytogenetic abnormalities, gene mutations, epigenetic modifications, gene expression patterns, and deregulated signaling pathways (e.g., apoptosis, proliferation, immune response, chromatin remodeling, RNA-splicing machinery, oxidative damage/DNA repair, microenvironment interactions, and others) associated with the disease. In this review, we discuss the contributions of noncoding RNAs (ncRNAs) to the pathogenesis of MDS as well as their potential applications as novel molecular markers for clinical purposes.

#### 2. Noncoding RNAs

At the end of the last millennium, the importance of noncoding RNAs was completely unknown. Up to that point, the scientific community focused on genes that coded for proteins. The classic dogma of molecular biology postulated that DNA was transcribed into RNA, which was then translated into protein, ignoring all non-protein-coding sequences. Only in 1993 did the importance of miRNAs begin to be revealed. The discovery of the first miRNA, lin-4, from Caenorhabditis elegans [4, 5] initiated a new scientific era that definitively overcame the absolute sanctity of the central dogma. Interest in this field was further stimulated by the finding that almost all of the mammalian genome was transcribed at some level [6], raising speculation that much of this pervasive transcription was likely functional. This idea was epitomized by the ENCODE (Encyclopedia of DNA Elements, www.encodeproject.org) consortium that claimed to have assigned "biochemical functions for 80% of the genome" [7, 8]. From the beginning of this era, researchers identified thousands of previously unknown types of noncoding RNAs and indeed started to reveal their multiple functions affecting various features of cells.

#### 2.1 Types of noncoding RNAs

Functional ncRNAs can be divided into two main types: infrastructural and regulatory ncRNAs. Infrastructural ncRNAs appear to have housekeeping roles in translation and splicing; they include species such as ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), and small nuclear RNAs (snRNAs) that are involved in splicing events. Regulatory ncRNAs, including long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and piwi-interacting RNAs (piRNAs) are involved in the modification and interactions with other RNAs. However, ncRNAs can also be categorized on the basis of length (small, 18–31 nt; medium, 31–200 nt; and long, >200 nt), structure (circular RNAs (circRNAs)), or subcellular localization (small nuclear RNAs (snRNAs) and small nucleolar RNAs (snoRNAs)). Other infrequent ncRNA types such as trans-spliced transcripts and macroRNAs that comprise enormous genomic distances, or multigene transcripts containing several genes or even the whole chromosome, further complicate efforts at systematic classification [9]. Moreover, clear categorization of ncRNA species is difficult, as many ncRNA transcripts often share properties of several categories. The major classes of ncRNAs are summarized in Table 1.

Of the various classes of ncRNAs, miRNAs and lncRNAs are the most numerous

A non–protein-coding transcript with >200 nt >200 nt

concerning miRNAs and lncRNAs are shown in Figure 1). Having different regulatory functions, these types of ncRNAs are important players in the majority of cellular processes, including hematopoiesis, and their abnormal function has serious implications for phenotypes. Deregulation of miRNAs and lncRNAs is frequently found in hematopoietic disorders, contributing substantially to the disease development and progression. Therefore, the following sections of this review will primarily focus on these two categories of ncRNAs and their functions in MDS.

miRNAs are short single-stranded noncoding RNA molecules of approximately 21–25 nt in length. Their sequences are highly conserved in both plants and animals and are thought to be an evolutionarily ancient component of gene regulation. miRNAs posttranscriptionally regulate gene expression through the RNA

and are probably the best-known ncRNA groups (numbers of publications

ncRNA class Description Description Length

ribosome

construction

RNA (scaRNA)

miRNA microRNA A short single-stranded RNA that usually

pathways

RNA that is directly incorporated into the

Transfer amino acids to the ribosome for protein

functions. Also commonly referred to as U-RNAs

RNA located in the nucleolus, mostly involved in modification of other RNAs, such as rRNA (C/Dbox and H/ACA box snoRNAs) or spliceosomal

suppresses the translation of target mRNA by binding to 3′ UTR through RNA interference

Double-stranded RNA that guides sequencespecific degradation of target mRNA through

A large class of small ncRNAs involved in retrotransposon silencing through interactions

complex, repressing its activity. It is also required

RNA derived from precursor mRNAs forming covalently closed continuous loop. It is more resistant to exonuclease-mediated degradation

RNA interference pathway

with piwi proteins

for DNA replication

Y-RNA Y RNA Components of the Ro ribonucleoprotein

Small RNA located in the nucleus, involved in spliceosomes (e.g., U1, U2, U5, U4, and U6), RNA modification, and other

Large subunit (5S–121 nt, 5.8S–156 nt, 28S–5070 nt) Small subunit (18S–1869 nt)

76–90 nt

150 nt

60–250 nt

21–25 nt

10–25 bp

26–31 nt

69–112 nt

1–5 exons

rRNA Ribosomal RNA

tRNA Transfer

snRNA Small

snoRNA Small

siRNA Small

piRNA Piwi-

circRNA Circular

lncRNA Long

The major categories of ncRNAs.

Table 1.

RNA

noncoding RNA

RNA

Noncoding RNAs in Myelodysplastic Syndromes DOI: http://dx.doi.org/10.5772/intechopen.79767

> nuclear RNA

nucleolar RNA

interfering RNA

interacting RNA

3. MicroRNAs

87

Noncoding RNAs in Myelodysplastic Syndromes DOI: http://dx.doi.org/10.5772/intechopen.79767


Table 1.

with specific clinical features and poor overall survival, independent of established risk factors [2]. Even though approximately 78% of MDS patients carry at least one oncogenic mutation [3], there is a long list of mutations in more than 50 genes with often unclear etiology, complicating the use of somatic mutations as simple and

Concerning MDS pathogenesis, substantial progress has been made in recent years. A vast literature has become available regarding the spectrum of cytogenetic abnormalities, gene mutations, epigenetic modifications, gene expression patterns,

response, chromatin remodeling, RNA-splicing machinery, oxidative damage/DNA repair, microenvironment interactions, and others) associated with the disease. In this review, we discuss the contributions of noncoding RNAs (ncRNAs) to the pathogenesis of MDS as well as their potential applications as novel molecular

At the end of the last millennium, the importance of noncoding RNAs was completely unknown. Up to that point, the scientific community focused on genes that coded for proteins. The classic dogma of molecular biology postulated that DNA was transcribed into RNA, which was then translated into protein, ignoring all non-protein-coding sequences. Only in 1993 did the importance of miRNAs begin to be revealed. The discovery of the first miRNA, lin-4, from Caenorhabditis elegans [4, 5] initiated a new scientific era that definitively overcame the absolute sanctity of the central dogma. Interest in this field was further stimulated by the finding that almost all of the mammalian genome was transcribed at some level [6], raising speculation that much of this pervasive transcription was likely func-

tional. This idea was epitomized by the ENCODE (Encyclopedia of DNA Elements, www.encodeproject.org) consortium that claimed to have assigned "biochemical functions for 80% of the genome" [7, 8]. From the beginning of this era, researchers identified thousands of previously unknown types of noncoding RNAs and indeed started to reveal their multiple functions affecting various fea-

Functional ncRNAs can be divided into two main types: infrastructural and regulatory ncRNAs. Infrastructural ncRNAs appear to have housekeeping roles in translation and splicing; they include species such as ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), and small nuclear RNAs (snRNAs) that are involved in splicing events. Regulatory ncRNAs, including long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and piwi-interacting RNAs (piRNAs) are involved in the modification and interactions with other RNAs. However, ncRNAs can also be categorized on the basis of length (small, 18–31 nt; medium, 31–200 nt; and long, >200 nt), structure (circular RNAs (circRNAs)), or subcellular localization (small nuclear RNAs (snRNAs) and small nucleolar RNAs (snoRNAs)). Other infrequent ncRNA types such as trans-spliced transcripts and macroRNAs that comprise enormous genomic distances, or multigene transcripts containing several genes or even the whole chromosome, further complicate efforts at systematic classification [9]. Moreover, clear categorization of ncRNA species is difficult, as many ncRNA transcripts often share properties of several categories. The major classes of ncRNAs are

and deregulated signaling pathways (e.g., apoptosis, proliferation, immune

universal markers of MDS prognosis.

Recent Developments in Myelodysplastic Syndromes

markers for clinical purposes.

2. Noncoding RNAs

tures of cells.

2.1 Types of noncoding RNAs

summarized in Table 1.

86

The major categories of ncRNAs.

Of the various classes of ncRNAs, miRNAs and lncRNAs are the most numerous and are probably the best-known ncRNA groups (numbers of publications concerning miRNAs and lncRNAs are shown in Figure 1). Having different regulatory functions, these types of ncRNAs are important players in the majority of cellular processes, including hematopoiesis, and their abnormal function has serious implications for phenotypes. Deregulation of miRNAs and lncRNAs is frequently found in hematopoietic disorders, contributing substantially to the disease development and progression. Therefore, the following sections of this review will primarily focus on these two categories of ncRNAs and their functions in MDS.

#### 3. MicroRNAs

miRNAs are short single-stranded noncoding RNA molecules of approximately 21–25 nt in length. Their sequences are highly conserved in both plants and animals and are thought to be an evolutionarily ancient component of gene regulation. miRNAs posttranscriptionally regulate gene expression through the RNA

into the silencing complex, the miRNA pairs with messenger RNA (mRNA) to direct posttranscriptional repression. At sites with extensive pairing complementarity, the miRNA directs argonaute-catalyzed mRNA cleavage. More commonly, however, the miRNAs direct translational repression, mRNA destabilization, or a

tissue miRNAs correlate with various pathophysiological conditions [16].

It has been shown that an individual miRNA is able to control the expression of more than one target mRNA and that each mRNA may be regulated by several miRNAs. Generally, it is believed that miRNAs regulate more than 30% of proteincoding genes in the human genome [11]. The ability of miRNAs to interact with thousands of mRNAs has raised intensive interest in their role in physiological and pathological conditions. Like mRNAs, the majority of miRNAs are expressed in tissue-specific manners. For example, miR-122 is preferentially expressed in liver [12], miR-124 in neurological tissues [13], miR-133 in muscles [14], and miR-208a in heart [15]. Moreover, it has been demonstrated that changes in the spectrum of

In recent years, cell-free circulating miRNAs have been found in various body fluids such as blood, cerebrospinal fluid, saliva, and urine [17]. The first extracellular small RNAs were observed in blood in 2004 [18]. Unlike the comprehensively described function of cellular miRNAs, the function of miRNAs present in the extracellular environment remains somewhat speculative. However, a growing body of evidence has suggested that these molecules are not mere leftovers of cellular degradation without any specific functions, but that active exchange of miRNAs between cells can play an important role in long-distance cell-to-cell com-

In 2008, Mitchell et al. [19] reported that extracellular miRNAs were stable in human plasma/serum. This high stability of circulating miRNAs despite high levels of RNase activity in blood indicates that circulating miRNAs must somehow be protected from degradation. To date, a number of miRNA carriers have been described: membrane-derived vesicles (shedding vesicles, exosomes), lipoproteins, and ribonucleoprotein complexes (with argonaute-2 (AGO2) or nucleophosmin 1 (NPM1) proteins) have been found to transport extracellular miRNAs. It has been reported that the sorting of miRNAs into various types of vesicles can be selective. Diehl et al. [20] compared the content of miRNAs in microvesicles and their maternal cells. These authors demonstrated a significantly varied spectrum of miRNAs in both samples, suggesting a selective packaging of miRNAs into

The differentiation and homeostasis of the hematopoietic system requires complex and interconnected molecular networks that need careful regulation. During the last decade, the role of miRNAs in the hematopoietic system has been extensively studied, and many miRNAs serving as critical regulators of both normal

The first study of a role of miRNAs in the differentiation of the immune system showed that forced expression of miR-181 in hematopoietic stem cells (HSCs) markedly increased the number of B lymphocytes, with a concomitant reduction of T lymphocytes [21]. Since then, other miRNAs specific for the maintenance of the "stemness" of HSCs and for the development of individual blood cell lines have been determined. For example, miR-125a was found to be sufficient as a single miRNA to

immune functions and diseases have been discovered (Figure 2).

combination of the two [10].

Noncoding RNAs in Myelodysplastic Syndromes DOI: http://dx.doi.org/10.5772/intechopen.79767

3.1 Extracellular miRNAs

munication.

microvesicles.

89

3.2 miRNAs in normal hematopoiesis

Figure 1.

Numbers of publications found on Pubmed using search terms: (a) miRNA (b) lncRNA, (c) MDS and miRNA, and (d) MDS and lncRNA (since the year 2000).

interference pathway. During the last decade, it has repeatedly been proven that miRNAs play crucial roles in a wide variety of biological processes such as development, differentiation, proliferation, and apoptosis. Because miRNAs influence the expression of genes involved in fundamental signaling pathways, their deregulation often triggers various pathological processes, including cardiovascular diseases, neurological diseases, and cancer.

The first miRNA, lin-4 from Caenorhabditis elegans, was discovered in the early 1990s [4, 5]. However, miRNAs were not recognized as a distinct class of biological regulators until the early 2000s. To date, thousands of miRNAs have been identified in humans and other species, and miRNA online sequence repositories, such as the miRBase database (www.mirbase.org), are available. According to the current version of the miRBase database (release 22), there are 1982 precursor miRNAs and 2693 mature miRNAs known in humans.

The biogenesis of miRNAs is a multistep process. miRNA genes are transcribed from genomic DNA by RNA polymerase II, resulting in primary miRNA (primiRNA) transcripts that usually encode sequences for several miRNAs. In the nucleus, these pri-miRNAs are cleaved by endonuclease Drosha, releasing approximately 70 nucleotide-long hairpin precursor miRNAs (pre-miRNAs). Pre-miRNAs are transported into the cytoplasm, where they are cleaved by Dicer into dsRNA duplexes containing both mature miRNA strand (miRNA) and its complementary strand (miRNA\*). In general, the mature miRNA strands are preferentially loaded into the miRNA-induced silencing complex (miRISC), whereas the complementary strands are excluded and degraded. Once processed from the hairpin and loaded

Noncoding RNAs in Myelodysplastic Syndromes DOI: http://dx.doi.org/10.5772/intechopen.79767

into the silencing complex, the miRNA pairs with messenger RNA (mRNA) to direct posttranscriptional repression. At sites with extensive pairing complementarity, the miRNA directs argonaute-catalyzed mRNA cleavage. More commonly, however, the miRNAs direct translational repression, mRNA destabilization, or a combination of the two [10].

It has been shown that an individual miRNA is able to control the expression of more than one target mRNA and that each mRNA may be regulated by several miRNAs. Generally, it is believed that miRNAs regulate more than 30% of proteincoding genes in the human genome [11]. The ability of miRNAs to interact with thousands of mRNAs has raised intensive interest in their role in physiological and pathological conditions. Like mRNAs, the majority of miRNAs are expressed in tissue-specific manners. For example, miR-122 is preferentially expressed in liver [12], miR-124 in neurological tissues [13], miR-133 in muscles [14], and miR-208a in heart [15]. Moreover, it has been demonstrated that changes in the spectrum of tissue miRNAs correlate with various pathophysiological conditions [16].

#### 3.1 Extracellular miRNAs

In recent years, cell-free circulating miRNAs have been found in various body fluids such as blood, cerebrospinal fluid, saliva, and urine [17]. The first extracellular small RNAs were observed in blood in 2004 [18]. Unlike the comprehensively described function of cellular miRNAs, the function of miRNAs present in the extracellular environment remains somewhat speculative. However, a growing body of evidence has suggested that these molecules are not mere leftovers of cellular degradation without any specific functions, but that active exchange of miRNAs between cells can play an important role in long-distance cell-to-cell communication.

In 2008, Mitchell et al. [19] reported that extracellular miRNAs were stable in human plasma/serum. This high stability of circulating miRNAs despite high levels of RNase activity in blood indicates that circulating miRNAs must somehow be protected from degradation. To date, a number of miRNA carriers have been described: membrane-derived vesicles (shedding vesicles, exosomes), lipoproteins, and ribonucleoprotein complexes (with argonaute-2 (AGO2) or nucleophosmin 1 (NPM1) proteins) have been found to transport extracellular miRNAs. It has been reported that the sorting of miRNAs into various types of vesicles can be selective. Diehl et al. [20] compared the content of miRNAs in microvesicles and their maternal cells. These authors demonstrated a significantly varied spectrum of miRNAs in both samples, suggesting a selective packaging of miRNAs into microvesicles.

#### 3.2 miRNAs in normal hematopoiesis

The differentiation and homeostasis of the hematopoietic system requires complex and interconnected molecular networks that need careful regulation. During the last decade, the role of miRNAs in the hematopoietic system has been extensively studied, and many miRNAs serving as critical regulators of both normal immune functions and diseases have been discovered (Figure 2).

The first study of a role of miRNAs in the differentiation of the immune system showed that forced expression of miR-181 in hematopoietic stem cells (HSCs) markedly increased the number of B lymphocytes, with a concomitant reduction of T lymphocytes [21]. Since then, other miRNAs specific for the maintenance of the "stemness" of HSCs and for the development of individual blood cell lines have been determined. For example, miR-125a was found to be sufficient as a single miRNA to

interference pathway. During the last decade, it has repeatedly been proven that miRNAs play crucial roles in a wide variety of biological processes such as development, differentiation, proliferation, and apoptosis. Because miRNAs influence the expression of genes involved in fundamental signaling pathways, their deregulation often triggers various pathological processes, including cardiovascular diseases,

Numbers of publications found on Pubmed using search terms: (a) miRNA (b) lncRNA, (c) MDS and

The first miRNA, lin-4 from Caenorhabditis elegans, was discovered in the early 1990s [4, 5]. However, miRNAs were not recognized as a distinct class of biological regulators until the early 2000s. To date, thousands of miRNAs have been identified in humans and other species, and miRNA online sequence repositories, such as the miRBase database (www.mirbase.org), are available. According to the current version of the miRBase database (release 22), there are 1982 precursor miRNAs and

The biogenesis of miRNAs is a multistep process. miRNA genes are transcribed

from genomic DNA by RNA polymerase II, resulting in primary miRNA (primiRNA) transcripts that usually encode sequences for several miRNAs. In the nucleus, these pri-miRNAs are cleaved by endonuclease Drosha, releasing approximately 70 nucleotide-long hairpin precursor miRNAs (pre-miRNAs). Pre-miRNAs are transported into the cytoplasm, where they are cleaved by Dicer into dsRNA duplexes containing both mature miRNA strand (miRNA) and its complementary strand (miRNA\*). In general, the mature miRNA strands are preferentially loaded into the miRNA-induced silencing complex (miRISC), whereas the complementary strands are excluded and degraded. Once processed from the hairpin and loaded

neurological diseases, and cancer.

miRNA, and (d) MDS and lncRNA (since the year 2000).

Recent Developments in Myelodysplastic Syndromes

Figure 1.

88

2693 mature miRNAs known in humans.

Several publications involved investigations of the role of miRNAs in AML. miRNA expression profiling revealed marked differences in miRNA expression between common cytogenetic subtypes of AML. Jongen-Lavrencic et al. [29] identified upregulation of several miRNAs (miR-382, miR-134, miR-376a, miR-127, miR-299-5p, and miR-323) in AML patients with t(15;17) and significant

downregulation of miRNAs from let-7 family in AML with t(8;21) as well as in AML with inv(16). Moreover, miRNA signatures have been reported to be associated with recurrent molecular abnormalities in cytogenetically normal AML [30]. For

downregulation of miR-204 and miR-128a were found in AML with NPM1 mutations [31] and high expression of miR-181a and miR-181b was associated with

Several preliminary reports focused on identification of miRNA expression profiles that were either common in MDS or specific for individual MDS subcategories. For example, Pons et al. [33] measured levels of expression of 25 mature miRNAs in mononuclear cells (MNCs) of MDS patients. The authors reported overexpression of miRNA cluster miR-17-92 in MDS and differential expression of miR-15a and miR-16 between low- and high-risk subgroups of patients. Hussein et al. [34] showed that the miRNA profiles in BM cells discriminated MDS with chromosomal alterations from patients with normal karyotypes. Sokol et al. [35] examined miRNA signature in BM MNCs and found deregulation of several miRNAs (increase of miR-222 and miR-10a; decrease of miR-146a, miR-150, and let-7e) in MDS. In our study, we analyzed miRNA expression on a genome-wide level in CD34+ BM cells. We observed significant differences in miRNA expression between early and advanced MDS; an apparent changeover was found between MDS with excess blast

example, upregulation of miR-10, let-7, and miR-29 family members and

1 (MDS-EB1) and MDS-EB2 subtypes. In particular, we identified strong upregulation of proapoptotic miR-34a in early subtypes of MDS [36].

between the protocols and platforms used for miRNA detection.

Although many studies were conducted regarding miRNA profiling in MDS, there have been very few overlaps among them. This inconsistency may mirror the heterogeneity of the disease but also may possibly be explained by variations

There are several lines of evidence that many miRNAs are deregulated in MDS; however, the functions of miRNAs in MDS pathogenesis remain rather unknown. Identification of target genes of miRNAs in MDS and their functional proofs in both in vitro cell cultures and in vivo animal models are necessary to realizing this goal.

One of the best-characterized MDS subtypes is MDS with isolated del(5q), formerly referred to as 5q− syndrome. Haploinsufficiency of specific genes within common deleted region (CDR) localized in 5q31.3-5q33 locus is essential for the specific phenotype of MDS with del(5q). In addition to protein-coding genes, 13 genes encoding miRNAs are located in CDR. Most importantly, Starczynowski et al. [37] correlated del(5q) haploinsufficiency with loss of two miRNAs that are abundant in hematopoietic stem/progenitor cells (HSPCs), miR-145 and miR-146a. Knockdown of miR-145 and miR-146a together in mouse HSPCs resulted in thrombocytosis, mild neutropenia, and megakaryocytic dysplasia [37].

Kumar et al. [38] showed that miR-145 loss in MDS with del(5q) affects megakaryocyte and erythroid differentiation. These authors found that miR-145 functions through the repression of FLI1 (Friend Leukemia Integration 1 Transcription

CEBPA (CCAAT/enhancer binding protein alpha) mutations [32].

3.4 miRNA deregulation in MDS

Noncoding RNAs in Myelodysplastic Syndromes DOI: http://dx.doi.org/10.5772/intechopen.79767

3.4.1 miRNAs in MDS with del(5q)

91

#### Figure 2.

Schema of lineage differentiation in hematopoiesis and miRNAs involved in the process. CLP—common lymphoid progenitor, CMP—common myeloid progenitor, ETP—early thymic progenitor, GMP—granulocyte macrophage progenitor, HSC—hematopoietic stem cell, MEP—megakaryocyte erythroid progenitor, NK—natural killer cell, RBC—red blood cell.

modulate HSC self-renewal and numbers and to protect lineage-negative progenitor cells from apoptosis [22]. A key miRNA that regulates granulocytic differentiation and function is miR-223. This miRNA shows a highly lineage-specific pattern of expression with low levels in HSCs and common myeloid progenitors. The expression of this miRNA is steadily upregulated during differentiation to granulocytes and is repressed during differentiation to the alternative monocytic fate [23]. miR-451 is expressed predominantly in erythroid cells, and its expression is significantly increased during maturation of erythrocytes. In contrast, miR-221 and miR-222 are downregulated during erythroid differentiation. This downregulation enables the expression of their target gene KIT (KIT proto-oncogene receptor tyrosine kinase, CD117), whose activation triggers erythroblast expansion [24]. Another miRNA, miR-150, is highly expressed in mature lymphocytes, whereas it is not active in HSCs. The target gene of miR-150 is transcription factor MYB (myeloblastosis) that regulates lymphocyte development [25]. miR-155, with its high levels in activated B cells, T cells, and monocytes, also participates in lymphoid differentiation. The development of B cells is positively regulated by miRNAs encoded by cluster miR-17-92. This cluster of miRNAs inhibits the expression of the apoptotic gene BIM (proapoptotic BH3-only Bcl-2 family member) and thus plays a key role in pro-B cells to pre-B cells transition [26]. In our laboratory, we analyzed miRNA expression in individual cell types from the peripheral blood of healthy individuals and determined a panel of 13 miRNAs whose expression profile enables differentiation of individual blood cell lines and determination of the cellular origin of in vitro cultured lines [27].

#### 3.3 miRNAs in malignant hematopoiesis

In oncogenesis, miRNAs act both as oncogenes and as tumor suppressors. Mechanisms of deregulation are similar to those of protein-coding genes (chromosome aberrations, mutations, and epigenetic modifications). In 2002, the loss of two miRNAs (miR-15a and miR-16-1) due to a deletion in the 13q14 region in patients with chronic lymphocytic leukemia was described for the first time as directly associated with malignant disease [28]. In subsequent years, several miRNAs with key roles in the pathogenesis and prognosis of hematological malignancies were detected.

Noncoding RNAs in Myelodysplastic Syndromes DOI: http://dx.doi.org/10.5772/intechopen.79767

Several publications involved investigations of the role of miRNAs in AML. miRNA expression profiling revealed marked differences in miRNA expression between common cytogenetic subtypes of AML. Jongen-Lavrencic et al. [29] identified upregulation of several miRNAs (miR-382, miR-134, miR-376a, miR-127, miR-299-5p, and miR-323) in AML patients with t(15;17) and significant downregulation of miRNAs from let-7 family in AML with t(8;21) as well as in AML with inv(16). Moreover, miRNA signatures have been reported to be associated with recurrent molecular abnormalities in cytogenetically normal AML [30]. For example, upregulation of miR-10, let-7, and miR-29 family members and downregulation of miR-204 and miR-128a were found in AML with NPM1 mutations [31] and high expression of miR-181a and miR-181b was associated with CEBPA (CCAAT/enhancer binding protein alpha) mutations [32].

#### 3.4 miRNA deregulation in MDS

Several preliminary reports focused on identification of miRNA expression profiles that were either common in MDS or specific for individual MDS subcategories. For example, Pons et al. [33] measured levels of expression of 25 mature miRNAs in mononuclear cells (MNCs) of MDS patients. The authors reported overexpression of miRNA cluster miR-17-92 in MDS and differential expression of miR-15a and miR-16 between low- and high-risk subgroups of patients. Hussein et al. [34] showed that the miRNA profiles in BM cells discriminated MDS with chromosomal alterations from patients with normal karyotypes. Sokol et al. [35] examined miRNA signature in BM MNCs and found deregulation of several miRNAs (increase of miR-222 and miR-10a; decrease of miR-146a, miR-150, and let-7e) in MDS. In our study, we analyzed miRNA expression on a genome-wide level in CD34+ BM cells. We observed significant differences in miRNA expression between early and advanced MDS; an apparent changeover was found between MDS with excess blast 1 (MDS-EB1) and MDS-EB2 subtypes. In particular, we identified strong upregulation of proapoptotic miR-34a in early subtypes of MDS [36].

Although many studies were conducted regarding miRNA profiling in MDS, there have been very few overlaps among them. This inconsistency may mirror the heterogeneity of the disease but also may possibly be explained by variations between the protocols and platforms used for miRNA detection.

There are several lines of evidence that many miRNAs are deregulated in MDS; however, the functions of miRNAs in MDS pathogenesis remain rather unknown. Identification of target genes of miRNAs in MDS and their functional proofs in both in vitro cell cultures and in vivo animal models are necessary to realizing this goal.

#### 3.4.1 miRNAs in MDS with del(5q)

One of the best-characterized MDS subtypes is MDS with isolated del(5q), formerly referred to as 5q− syndrome. Haploinsufficiency of specific genes within common deleted region (CDR) localized in 5q31.3-5q33 locus is essential for the specific phenotype of MDS with del(5q). In addition to protein-coding genes, 13 genes encoding miRNAs are located in CDR. Most importantly, Starczynowski et al. [37] correlated del(5q) haploinsufficiency with loss of two miRNAs that are abundant in hematopoietic stem/progenitor cells (HSPCs), miR-145 and miR-146a. Knockdown of miR-145 and miR-146a together in mouse HSPCs resulted in thrombocytosis, mild neutropenia, and megakaryocytic dysplasia [37].

Kumar et al. [38] showed that miR-145 loss in MDS with del(5q) affects megakaryocyte and erythroid differentiation. These authors found that miR-145 functions through the repression of FLI1 (Friend Leukemia Integration 1 Transcription

modulate HSC self-renewal and numbers and to protect lineage-negative progenitor cells from apoptosis [22]. A key miRNA that regulates granulocytic differentiation and function is miR-223. This miRNA shows a highly lineage-specific pattern of expression with low levels in HSCs and common myeloid progenitors. The expression of this miRNA is steadily upregulated during differentiation to granulocytes and is repressed during differentiation to the alternative monocytic fate [23]. miR-451 is expressed predominantly in erythroid cells, and its expression is significantly increased during maturation of erythrocytes. In contrast, miR-221 and miR-222 are downregulated during erythroid differentiation. This downregulation enables the expression of their target gene KIT (KIT proto-oncogene receptor tyrosine kinase, CD117), whose activation triggers erythroblast expansion [24]. Another miRNA, miR-150, is highly expressed in mature lymphocytes, whereas it is not active in HSCs. The target gene of miR-150 is transcription factor MYB (myeloblastosis) that regulates lymphocyte development [25]. miR-155, with its high levels in activated B cells, T cells, and monocytes, also participates in lymphoid differentiation. The development of B cells is positively regulated by miRNAs encoded by cluster miR-17-92. This cluster of miRNAs inhibits the expression of the apoptotic gene BIM (proapoptotic BH3-only Bcl-2 family member) and thus plays a key role in pro-B cells to pre-B cells transition [26]. In our laboratory, we analyzed miRNA expression in individual cell types from the peripheral blood of healthy individuals and determined a panel of 13 miRNAs whose expression profile enables differentiation of individual blood cell lines and determination of the cellular origin of in vitro cultured lines [27].

Schema of lineage differentiation in hematopoiesis and miRNAs involved in the process. CLP—common lymphoid progenitor, CMP—common myeloid progenitor, ETP—early thymic progenitor, GMP—granulocyte macrophage progenitor, HSC—hematopoietic stem cell, MEP—megakaryocyte erythroid progenitor,

In oncogenesis, miRNAs act both as oncogenes and as tumor suppressors. Mechanisms of deregulation are similar to those of protein-coding genes (chromosome aberrations, mutations, and epigenetic modifications). In 2002, the loss of two miRNAs (miR-15a and miR-16-1) due to a deletion in the 13q14 region in patients with chronic lymphocytic leukemia was described for the first time as directly associated with malignant disease [28]. In subsequent years, several miRNAs with key roles in the pathogenesis and prognosis of hematological malignancies were

3.3 miRNAs in malignant hematopoiesis

detected.

90

Figure 2.

NK—natural killer cell, RBC—red blood cell.

Recent Developments in Myelodysplastic Syndromes

#### Recent Developments in Myelodysplastic Syndromes

Factor), a megakaryocyte and erythroid regulatory transcription factor. Inhibition of miR-145 increases the production of megakaryocytic cells relative to that of erythroid cells. Moreover, the authors proved that combined loss of miR-145 and RPS14 (a ribosomal gene that is required for the maturation of 40S ribosomal subunits and that maps to the CDR) cooperates to alter erythroid-megakaryocytic differentiation in a manner similar to that of the 5q− syndrome [38].

and AML with myelodysplasia-related changes. Several studies investigated miRNA expression with respect to HMA treatment in AML [45–47]. Blum et al. [45] proposed miR-29b as a predictive factor for the stratification of older AML patients treated with decitabine; however, this was not confirmed by other studies [46]. Butrym et al. [47] showed that low expression of miR-181 at diagnosis was a predictor of complete remission and prolonged survival in a subset of older AML

In relation to HMA therapy in MDS, it was found that the level of extracellular miR-21 was associated with overall response rate and progression-free survival [48]. Furthermore, reduced expression of miR-124 (caused by abnormal methylation) was found in MDS/AML patients responding to decitabine. These patients exhibited significantly lower expression levels of the CDK6 gene (cyclin-dependent kinase 6) that is the target of miR-124 [49]. Moreover, hypermethylation of miR-124-3p gene appeared to be a good prognostic marker of overall survival [50]. In our report, we found that the overall response rate to azacitidine treatment was significantly higher in MDS/AML patients with upregulated miR-17-3p and downregulated miR-100-5p and miR-133b and that the high level of miR-100-5p was associated

To date, only a few studies have investigated circulating miRNAs in MDS [48, 52–54]. Two papers [48, 52] focused on specific circulating miRNAs (miR-21, let-7a, and miR-16) that were preselected based on information regarding their deregulation in blood cells and their importance in similar diseases. Researchers monitored the plasma/serum levels of these miRNAs and showed that their levels could serve as prognostic markers for MDS. Kim et al. [48] showed that serum level of miR-21 was significantly associated with overall response rate and progression-free survival in MDS patients treated with HMAs. The publication that studied let-7a and miR-16 demonstrated that high plasma levels of these miRNAs can serve as semi-invasive

Zuo et al. [53] measured expression of 800 human miRNAs in MDS plasma. These authors identified a 7-miRNA signature (let-7a, miR-144, miR-16, miR-25, miR-451, miR-651, and miR-655) as an independent predictor of survival in MDS

In our study, we investigated the spectrum (2006 human miRNAs) of circulating miRNAs in the plasma of MDS patients [54]. With regard to prognosis, the levels of miR-27a-3p, miR-150-5p, miR-199a-5p, miR-223-3p, and miR-451a were lower in higher risk MDS. Moreover, miR-451a was an independent predictor of progression-free survival, and there was a significant association of miR-223-3p

These pioneer studies suggested that plasma levels of specific miRNAs were associated with MDS patient outcome and may add information beyond the currently used scoring systems. Despite these early promising results, there remain insufficient data regarding the full spectrum of extracellular RNAs in MDS. To date, the possible presence of various forms of small noncoding RNAs (apart from mature miRNAs), pathways for their protection, and identification of their cells of origin have not been explored in MDS. These missing information would expand the knowledge regarding extracellular RNAs in this disease, and beyond that, it would definitely contribute to better interpretation of alterations of individual miRNAs with the potential to become specific prognostic markers in MDS.

patients treated with azacitidine.

Noncoding RNAs in Myelodysplastic Syndromes DOI: http://dx.doi.org/10.5772/intechopen.79767

with shorter overall survival [51].

3.4.4 Extracellular miRNAs in MDS

patients with normal karyotypes.

with overall survival [54].

93

markers of poor outcome for MDS patients [52].

In our studies, we detected high expression of miR-34a in MDS del(5q) patients [36, 39]. The expression of miR-34a is induced by p53, activating apoptosis through inhibition of BCL2 gene (B-Cell CLL/Lymphoma 2, Apoptosis Regulator). This result is consistent with the increased apoptosis of progenitor cells seen in MDS del(5q).

#### 3.4.2 miRNAs related to prognosis of MDS

Several publications have focused on miRNA expression in MDS with regard to prognostic potential. The earliest study in this area associated miRNA profiles with the International Prognostic Scoring System (IPSS) score [35]. A unique signature consisting of 10 miRNAs was closely associated with IPSS risk category permitting discrimination between lower- and higher-risk disease. Selective overexpression of miR-181 family members was detected in higher risk MDS, indicating pathogenetic overlap with AML. Survival analysis revealed shorter survival in patients with high expression of miR-181 family than in patients with low miR-181 expression [35].

Another miRNA that has been identified as having prognostic value in MDS is miR-22 [40]. This miRNA was upregulated in MDS and its level correlated with poor survival. Transgenic mice expressing miR-22 in the hematopoietic cells displayed reduced levels of global 5-hydroxymethylcytosine and increased HSC self-renewal accompanied by defective differentiation. Over time, these mice developed MDS. Interestingly, TET2 gene (Ten-Eleven Translocation 2, Tet Methylcytosine Dioxygenase 2) was identified as a key target of miR-22 in this context [40]. TET2 is a major regulator of DNA demethylation by conversion of methylated cytosine into 5-hydroxymethylcytosine.

#### 3.4.3 miRNAs in the treatment of MDS

Expression profiles of miRNAs also appear to be applicable predictors of treatment responses. Lenalidomide is an immunomodulatory and antiangiogenic agent used for the treatment of MDS with del(5q). In recent years, several studies have analyzed miRNA expression levels before and after lenalidomide treatment in these patients [41–44]. Oliva et al. [41] investigated expression of selected genes/miRNAs at baseline and after 3 and 6 months of lenalidomide treatment. These authors showed that the expression levels of miR-145, miR-146, and miR-155 gradually increased during the course of the treatment. The significant role of miR-143 and miR-145 in response to lenalidomide was confirmed by Venner et al. [42], who showed that lenalidomide selectively abrogated progenitor activity in cells depleted of miR-143 and miR-145, supporting their key role in the sensitivity to lenalidomide in MDS with del(5q). In our studies, the most significant changes in expression levels (decreases) after lenalidomide treatment showed miR-34a and several miRNAs clustered within the 14q32 locus [43, 44]. However, a question remains as to whether the changes in expression levels were due to direct response to lenalidomide or whether they were caused by a reduction of the pathological clone.

Therapy with hypomethylating agents (HMAs) such as azacitidine and decitabine is currently considered to be the standard therapy for higher-risk MDS

#### Noncoding RNAs in Myelodysplastic Syndromes DOI: http://dx.doi.org/10.5772/intechopen.79767

Factor), a megakaryocyte and erythroid regulatory transcription factor. Inhibition of miR-145 increases the production of megakaryocytic cells relative to that of erythroid cells. Moreover, the authors proved that combined loss of miR-145 and RPS14 (a ribosomal gene that is required for the maturation of 40S ribosomal subunits and that maps to the CDR) cooperates to alter erythroid-megakaryocytic

In our studies, we detected high expression of miR-34a in MDS del(5q) patients [36, 39]. The expression of miR-34a is induced by p53, activating apoptosis through inhibition of BCL2 gene (B-Cell CLL/Lymphoma 2, Apoptosis Regulator). This result is consistent with the increased apoptosis of progenitor cells seen in MDS

Several publications have focused on miRNA expression in MDS with regard to prognostic potential. The earliest study in this area associated miRNA profiles with the International Prognostic Scoring System (IPSS) score [35]. A unique signature consisting of 10 miRNAs was closely associated with IPSS risk category permitting discrimination between lower- and higher-risk disease. Selective overexpression of miR-181 family members was detected in higher risk MDS, indicating pathogenetic overlap with AML. Survival analysis revealed shorter survival in patients with high expression of miR-181 family than in patients with low miR-181 expression [35]. Another miRNA that has been identified as having prognostic value in MDS is miR-22 [40]. This miRNA was upregulated in MDS and its level correlated with poor survival. Transgenic mice expressing miR-22 in the hematopoietic cells displayed reduced levels of global 5-hydroxymethylcytosine and increased HSC self-renewal accompanied by defective differentiation. Over time, these mice developed MDS. Interestingly, TET2 gene (Ten-Eleven Translocation 2, Tet Methylcytosine Dioxygenase 2) was identified as a key target of miR-22 in this context [40]. TET2 is a major regulator of DNA demethylation by conversion of

Expression profiles of miRNAs also appear to be applicable predictors of treatment responses. Lenalidomide is an immunomodulatory and antiangiogenic agent used for the treatment of MDS with del(5q). In recent years, several studies have analyzed miRNA expression levels before and after lenalidomide treatment in these patients [41–44]. Oliva et al. [41] investigated expression of selected genes/miRNAs at baseline and after 3 and 6 months of lenalidomide treatment. These authors showed that the expression levels of miR-145, miR-146, and miR-155 gradually increased during the course of the treatment. The significant role of miR-143 and miR-145 in response to lenalidomide was confirmed by Venner et al. [42], who showed that lenalidomide selectively abrogated progenitor activity in cells depleted of miR-143 and miR-145, supporting their key role in the sensitivity to lenalidomide in MDS with del(5q). In our studies, the most significant changes in expression levels (decreases) after lenalidomide treatment showed miR-34a and several miRNAs clustered within the 14q32 locus [43, 44]. However, a question remains as to whether the changes in expression levels were due to direct response to lenalidomide or whether they were caused by a reduction of the pathological clone. Therapy with hypomethylating agents (HMAs) such as azacitidine and decitabine is currently considered to be the standard therapy for higher-risk MDS

differentiation in a manner similar to that of the 5q− syndrome [38].

del(5q).

92

3.4.2 miRNAs related to prognosis of MDS

Recent Developments in Myelodysplastic Syndromes

methylated cytosine into 5-hydroxymethylcytosine.

3.4.3 miRNAs in the treatment of MDS

and AML with myelodysplasia-related changes. Several studies investigated miRNA expression with respect to HMA treatment in AML [45–47]. Blum et al. [45] proposed miR-29b as a predictive factor for the stratification of older AML patients treated with decitabine; however, this was not confirmed by other studies [46]. Butrym et al. [47] showed that low expression of miR-181 at diagnosis was a predictor of complete remission and prolonged survival in a subset of older AML patients treated with azacitidine.

In relation to HMA therapy in MDS, it was found that the level of extracellular miR-21 was associated with overall response rate and progression-free survival [48]. Furthermore, reduced expression of miR-124 (caused by abnormal methylation) was found in MDS/AML patients responding to decitabine. These patients exhibited significantly lower expression levels of the CDK6 gene (cyclin-dependent kinase 6) that is the target of miR-124 [49]. Moreover, hypermethylation of miR-124-3p gene appeared to be a good prognostic marker of overall survival [50]. In our report, we found that the overall response rate to azacitidine treatment was significantly higher in MDS/AML patients with upregulated miR-17-3p and downregulated miR-100-5p and miR-133b and that the high level of miR-100-5p was associated with shorter overall survival [51].

#### 3.4.4 Extracellular miRNAs in MDS

To date, only a few studies have investigated circulating miRNAs in MDS [48, 52–54]. Two papers [48, 52] focused on specific circulating miRNAs (miR-21, let-7a, and miR-16) that were preselected based on information regarding their deregulation in blood cells and their importance in similar diseases. Researchers monitored the plasma/serum levels of these miRNAs and showed that their levels could serve as prognostic markers for MDS. Kim et al. [48] showed that serum level of miR-21 was significantly associated with overall response rate and progression-free survival in MDS patients treated with HMAs. The publication that studied let-7a and miR-16 demonstrated that high plasma levels of these miRNAs can serve as semi-invasive markers of poor outcome for MDS patients [52].

Zuo et al. [53] measured expression of 800 human miRNAs in MDS plasma. These authors identified a 7-miRNA signature (let-7a, miR-144, miR-16, miR-25, miR-451, miR-651, and miR-655) as an independent predictor of survival in MDS patients with normal karyotypes.

In our study, we investigated the spectrum (2006 human miRNAs) of circulating miRNAs in the plasma of MDS patients [54]. With regard to prognosis, the levels of miR-27a-3p, miR-150-5p, miR-199a-5p, miR-223-3p, and miR-451a were lower in higher risk MDS. Moreover, miR-451a was an independent predictor of progression-free survival, and there was a significant association of miR-223-3p with overall survival [54].

These pioneer studies suggested that plasma levels of specific miRNAs were associated with MDS patient outcome and may add information beyond the currently used scoring systems. Despite these early promising results, there remain insufficient data regarding the full spectrum of extracellular RNAs in MDS. To date, the possible presence of various forms of small noncoding RNAs (apart from mature miRNAs), pathways for their protection, and identification of their cells of origin have not been explored in MDS. These missing information would expand the knowledge regarding extracellular RNAs in this disease, and beyond that, it would definitely contribute to better interpretation of alterations of individual miRNAs with the potential to become specific prognostic markers in MDS.

#### 4. Long noncoding RNAs

lncRNAs form perhaps the most numerous group of ncRNAs. These RNAs are defined as protein-noncoding transcripts longer than 200 nucleotides. This length was proposed to distinguish lncRNAs from small noncoding RNAs. In contrast with protein-coding RNAs, lncRNAs contain only short open reading frames or completely lack them. This group of ncRNAs is characterized by high levels of structural and functional diversity, low levels of GC nucleotides, and lower expression levels, in contrast with protein-coding transcripts. lncRNAs are transcribed by RNA polymerase II or III and subsequently can be spliced and polyadenylated at the <sup>3</sup>′ end or may contain a 5′ cap, depending on their biogenesis. Their expression is developmental and tissue-specific.

crucial for correct function of the hematopoietic system (Table 2). The first hematopoiesis-associated lncRNA, EGOT (Eosinophil Granule Ontogeny Transcript), was described in 2007. EGOT, a conserved transcript localized antisense to ITPR1 (Inositol 1,4,5-Trisphosphate Receptor Type 1) that modulates the development of eosinophils, is normally expressed in human CD34<sup>+</sup> HSCs, and its expression level increases during eosinophil development, helping to regulate production

The relatively well-known lncRNA, H19, maintains quiescence of adult HSCs. The H19 transcript was in fact the first lncRNA to be identified, enriched in the embryonic fetal liver but downregulated after birth [60]. H19 is active in long-term HSCs and becomes gradually downregulated in short-term HSCs and multipotent progenitors. Deletion of H19 from the maternal allele resulted in increased HSC activation and proliferation as well as impaired repopulating ability. This effect is mediated by derepression of maternal IGF2 (Insulin-Like Growth Factor 2) expression and by increased IGF1R (IGF1 Receptor) translation, resulting in increased

Zhang et al. [62] identified HOTAIRM1 (Homeobox Antisense Intergenic RNA Myeloid 1), which is encoded within the human HOXA (Homeobox A) gene cluster and plays a role in the differentiation of myeloid cells. The expression of this transcript is upregulated during granulocyte differentiation. Knockdown of HOTAIRM1 reduced transcription of HOXA1 and HOXA4 in an acute

promyelocytic leukemia cell line, resulting in a decreased expression of genes asso-

LncRNA Localization Function Reference

Modulates development of

Maintains quiescence of adult

Induces differentiation of

[59]

[60]

[62]

[63]

[67]

[68]

[69]

[73]

eosinophils

myeloid cells

maturation

Oncogene, promotes chromatin relocalization

15q26.3 Positive regulator of cell division

11q13.1 Regulates transcription and cell cycle

Xq13.2 Regulates X chromosome

14q32.2 Tumor suppressor [70]

inactivation during embryogenesis

HSCs

ciated with granulocyte activation, defense response, and maturation [62].

3p26.1, antisense to ITPR1 gene

7p15.2, encoded within the HOXA gene cluster

T-ALL-R-LncR1 6q24.3 Induces apoptosis in T-ALL [66]

lincRNA-EPS Mouse 4qC7 Promotes red blood cell

12q13.13, encoded within the HOXC gene

cluster

Examples of lncRNAs involved in normal and malignant hematopoiesis.

of eosinophil granule proteins [59].

Noncoding RNAs in Myelodysplastic Syndromes DOI: http://dx.doi.org/10.5772/intechopen.79767

signaling through the IGF1R [61].

(Eosinophil Granule Ontogeny

(Hox Antisense Intergenic RNA

(Leukemia-Induced Noncoding

(Hox Transcript Antisense

(Metastasis Associated Lung Adenocarcinoma Transcript)

(Maternally Expressed Gene 3)

(X-Inactive Specific Transcript)

H19 11p15.5, antisense to

IGF2

EGOT

Transcript)

HOTAIRM

Myeloid 1)

LUNAR1

HOTAIR

MALAT-1

RNA)

MEG3

XIST

Table 2.

95

Activator RNA)

Some lncRNAs regulate (negatively or positively) the expression of genes in trans or cis by affecting RNA polymerase II recruitment or by inducing chromatin remodeling. In addition, antisense transcripts can pair with their specific sense RNA, facilitating alternative splicing. When lncRNAs interact with proteins, they can influence protein activity or localization or even help to form cellular substructures or ribonucleoprotein complexes. lncRNAs can be processed to yield small, single- or double-stranded RNAs that can act as endogenous small interfering RNAs (siRNAs) or miRNAs. Moreover, they can also act as "miRNA sponges" that affect the competitive endogenous RNA (ceRNA) network. However, additional functions and detailed signaling pathways of lncRNAs remain to be clarified [55].

According to their position relative to protein-coding mRNAs, lncRNAs are further subcategorized into several groups. Long intergenic noncoding RNAs (lincRNAs) are lncRNAs that are located between annotated protein-coding genes and that are at least 1 kb away from the nearest protein-coding genes. Intronic lncRNAs are coded within introns of protein-coding genes. Sense and antisense lncRNAs are transcribed from the sense or antisense strands of protein-coding genes and often contain exons of this gene with mutual overlap. Bidirectional lncRNAs are oriented head-to-head with protein-coding genes within 1 kb. Bidirectional lncRNA transcripts often exhibit similar expression patterns to those of their protein-coding counterpart, suggesting that they may be subject to shared regulatory pressures. Another group of lncRNA is TERRA (Telomeric Repeat-Containing RNA), transcribed from constitutive heterochromatin-rich regions, or T-UCR (Transcribed Ultraconserved Regions), transcribed from highly conserved regions of the genome.

Although more than 100,000 lncRNAs have been identified to date, only a small number of them have been characterized in detail. To integrate the data describing various lncRNAs, their expression profiles, molecular features, and functions in a variety of cell systems, several databases containing a comprehensive list of lncRNAs have been developed and are continually being updated. Among the most comprehensive databases are LNCipedia (compendium of human lncRNAs, lncipedia.org) [56], lncRNAdb (reference database for functional lncRNAs, lncRNAdb.org) [57], and NRED (database of lncRNA expression, nred.matticklab. com) [58].

#### 4.1 lncRNAs in normal hematopoiesis

Recently, lncRNAs have emerged as important regulators of cell fate. These RNAs play a variety of roles in controlling various steps in hematopoietic differentiation, including maintenance of HSCs and differentiation of myeloid, erythroid, and lymphoid lineages. To date, there have been several descriptions of lncRNAs

#### Noncoding RNAs in Myelodysplastic Syndromes DOI: http://dx.doi.org/10.5772/intechopen.79767

4. Long noncoding RNAs

Recent Developments in Myelodysplastic Syndromes

developmental and tissue-specific.

of the genome.

com) [58].

94

4.1 lncRNAs in normal hematopoiesis

lncRNAs form perhaps the most numerous group of ncRNAs. These RNAs are defined as protein-noncoding transcripts longer than 200 nucleotides. This length was proposed to distinguish lncRNAs from small noncoding RNAs. In contrast with

Some lncRNAs regulate (negatively or positively) the expression of genes in trans or cis by affecting RNA polymerase II recruitment or by inducing chromatin remodeling. In addition, antisense transcripts can pair with their specific sense RNA, facilitating alternative splicing. When lncRNAs interact with proteins, they can influence protein activity or localization or even help to form cellular substructures or ribonucleoprotein complexes. lncRNAs can be processed to yield small, single- or double-stranded RNAs that can act as endogenous small interfering RNAs (siRNAs) or miRNAs. Moreover, they can also act as "miRNA sponges" that affect the competitive endogenous RNA (ceRNA) network. However, additional functions and detailed signaling pathways of lncRNAs remain to be clarified [55]. According to their position relative to protein-coding mRNAs, lncRNAs are further subcategorized into several groups. Long intergenic noncoding RNAs (lincRNAs) are lncRNAs that are located between annotated protein-coding genes and that are at least 1 kb away from the nearest protein-coding genes. Intronic lncRNAs are coded within introns of protein-coding genes. Sense and antisense lncRNAs are transcribed from the sense or antisense strands of protein-coding genes and often contain exons of this gene with mutual overlap. Bidirectional lncRNAs are oriented head-to-head with protein-coding genes within 1 kb. Bidirectional lncRNA transcripts often exhibit similar expression patterns to those of their protein-coding counterpart, suggesting that they may be subject to shared regulatory pressures. Another group of lncRNA is TERRA (Telomeric Repeat-Containing RNA), transcribed from constitutive heterochromatin-rich regions, or T-UCR (Transcribed Ultraconserved Regions), transcribed from highly conserved regions

Although more than 100,000 lncRNAs have been identified to date, only a small number of them have been characterized in detail. To integrate the data describing various lncRNAs, their expression profiles, molecular features, and functions in a variety of cell systems, several databases containing a comprehensive list of

lncRNAs have been developed and are continually being updated. Among the most comprehensive databases are LNCipedia (compendium of human lncRNAs, lncipedia.org) [56], lncRNAdb (reference database for functional lncRNAs, lncRNAdb.org) [57], and NRED (database of lncRNA expression, nred.matticklab.

Recently, lncRNAs have emerged as important regulators of cell fate. These RNAs play a variety of roles in controlling various steps in hematopoietic differentiation, including maintenance of HSCs and differentiation of myeloid, erythroid, and lymphoid lineages. To date, there have been several descriptions of lncRNAs

protein-coding RNAs, lncRNAs contain only short open reading frames or completely lack them. This group of ncRNAs is characterized by high levels of structural and functional diversity, low levels of GC nucleotides, and lower expression levels, in contrast with protein-coding transcripts. lncRNAs are transcribed by RNA polymerase II or III and subsequently can be spliced and polyadenylated at the <sup>3</sup>′ end or may contain a 5′ cap, depending on their biogenesis. Their expression is

crucial for correct function of the hematopoietic system (Table 2). The first hematopoiesis-associated lncRNA, EGOT (Eosinophil Granule Ontogeny Transcript), was described in 2007. EGOT, a conserved transcript localized antisense to ITPR1 (Inositol 1,4,5-Trisphosphate Receptor Type 1) that modulates the development of eosinophils, is normally expressed in human CD34<sup>+</sup> HSCs, and its expression level increases during eosinophil development, helping to regulate production of eosinophil granule proteins [59].

The relatively well-known lncRNA, H19, maintains quiescence of adult HSCs. The H19 transcript was in fact the first lncRNA to be identified, enriched in the embryonic fetal liver but downregulated after birth [60]. H19 is active in long-term HSCs and becomes gradually downregulated in short-term HSCs and multipotent progenitors. Deletion of H19 from the maternal allele resulted in increased HSC activation and proliferation as well as impaired repopulating ability. This effect is mediated by derepression of maternal IGF2 (Insulin-Like Growth Factor 2) expression and by increased IGF1R (IGF1 Receptor) translation, resulting in increased signaling through the IGF1R [61].

Zhang et al. [62] identified HOTAIRM1 (Homeobox Antisense Intergenic RNA Myeloid 1), which is encoded within the human HOXA (Homeobox A) gene cluster and plays a role in the differentiation of myeloid cells. The expression of this transcript is upregulated during granulocyte differentiation. Knockdown of HOTAIRM1 reduced transcription of HOXA1 and HOXA4 in an acute promyelocytic leukemia cell line, resulting in a decreased expression of genes associated with granulocyte activation, defense response, and maturation [62].


#### Table 2.

Examples of lncRNAs involved in normal and malignant hematopoiesis.

Hu et al. [63] studied the lncRNA transcriptome of the erythroid lineage and uncovered numerous erythroid-specific lncRNAs that become induced during terminal differentiation of mouse fetal liver red blood cells in vivo. These authors showed that lincRNA-EPS (erythroid prosurvival) acts to promote red blood cell maturation by downregulating proapoptotic pathways. Knockdown of lincRNA-EPS severely compromised terminal differentiation of erythroid progenitors and resulted in elevated apoptosis. Conversely, its ectopic expression protected erythroid progenitors from apoptosis triggered by erythropoietin starvation. Functional studies indicated that lincRNA-EPS acts by repressing a number of proapoptotic proteins, most prominently the caspase-activating adaptor protein Pycard [63].

demonstrated that mutant females developed a highly aggressive myeloproliferative

The first study examining the deregulation of lncRNAs on a genome-wide level in MDS was published in 2017 [74]. The authors combined NGS and microarray data in CD34<sup>+</sup> BM cells and identified several lncRNAs (linc-ARFIP1-4, linc-TAAR9-1, lincC2orf85, linc-RNFT2-1, and linc-RPIA) deregulated in MDS-EB2. In the same year, Yao et al. [75] profiled lncRNA expressions in 176 adult patients with primary MDS and identified four lncRNAs (TC07000551.hg.1, TC08000489.hg.1, TC02004770.hg.1, and TC03000701) with expression levels significantly associated with overall survival. Subsequently, the authors constructed a risk-scoring system with the weighted sum of these four lncRNAs. Higher lncRNA scores were associated with higher marrow blast percentages, higher-risk subtypes of MDS, complex cytogenetic changes, and mutations in RUNX1, ASXL1, TP53, SRSF2, and ZRSR2, whereas they were inversely correlated with the SF3B1 mutation. Patients with higher lncRNA scores had significantly shorter overall survival and higher 5-year

neoplasm and MDS (mixed MPN/MDS) with 100% penetrance.

Noncoding RNAs in Myelodysplastic Syndromes DOI: http://dx.doi.org/10.5772/intechopen.79767

leukemic transformation rate than did those with lower scores [75].

potential roles in pathophysiology [74].

5.1 Piwi-interacting RNAs

97

5. Other types of noncoding RNAs in MDS

particularly those involved in spermatogenesis.

studies indicated that the piwi-piRNA complex may have a role in

Although increasing numbers of deregulated lncRNAs are currently being described in MDS, only a few have been functionally characterized so far. Transcriptomic data may be used to construct network modules consisting of lncRNAs and protein-coding genes to enable functional analysis of lncRNAs with unknown functions. These networks are subsequently linked with annotated signaling pathways and gene ontologies. The resulting outputs provide a degree of functional annotation for differentially expressed lncRNAs in the disease and their

Only very limited information regarding other groups of ncRNAs have been published for MDS to date. However, we can anticipate that introduction of nextgeneration sequencing of RNAs (so-called RNA-seq) will bring to MDS research many novel insights regarding various ncRNAs in the near future. This technology enables sensitive global detection of various RNAs across an unparalleled dynamic range. Particularly, small RNA-seq is predominantly used for detection of miRNAs. However, during library preparation, small RNAs are selected by electrophoresis with sizes typically ranging from 20 to 50 nt. This range of size selection allows for

In 2011, Beck et al. [76] conducted one of the early studies to apply small RNAseq in MDS. These authors compared expression of small RNAs between low-grade (refractory anemia, RA) and high-grade (MDS-EB2) MDS patients and demonstrated the first evidence of piwi (P-element-Induced Wimpy Testis)-interacting RNAs (piRNAs) in MDS BM cells and their particular enrichment in low-grade MDS. PiRNAs are a relatively newly defined class of small ncRNAs with lengths from 26 to 32 nt. These RNAs lack sequence conservation and are more complex than miRNAs. PiRNAs have been linked to both epigenetic and posttranscriptional gene silencing of retrotransposons and other genetic elements in germline cells,

Transcription of particular piwi proteins (piwil1 and piwil2) that are required for the accumulation of piRNAs was also significantly upregulated in RA [76]. Recent

the capture of many other species of small RNAs in addition to miRNAs.

Recent studies have also provided evidence for the importance of several lncRNAs in immune cell function. For example, lncRNA NeST (Nettoie Salmonella pas Theiler's, cleanup Salmonella not Theiler's), also named Tmevpg1, modulates the ability of mice to respond to viral and bacterial infections. NeST is specifically expressed by the TH1 subset of helper T cells. The expression of NeST regulates the degree of inflammation induced by infecting pathogens, such as Thelier's virus or Salmonella [64]. lncRNA-Cox2 (cyclooxygenase 2) acts during inflammatory signaling by modulating the expression of several immune response genes via interactions with regulatory complexes [65].

#### 4.2 lncRNAs in malignant hematopoiesis

lncRNAs not only participate in normal hematopoiesis but also contribute to the pathogenesis of hematologic malignancies, representing a new class of potential biomarkers and therapeutic targets. These RNAs have significantly different expression levels in primary tumors and metastases, functioning both as oncogenes or as tumor suppressors. Some cancer-related lncRNAs could affect the development and progression of tumor by means of p53, polycomb repressive complex 2 (PRC2), and other signaling pathways. Others are not observed in normal tissue but are detected in cancer. For example, T-ALL-R-lncR1 appears to induce (together with protease-activated receptor 4 (PAR-4)) cellular apoptosis in T cell acute lymphoblastic leukemia cells (T-ALL) [66]. LUNAR1 (leukemia-induced noncoding activator RNA) is highly expressed in T-ALL cells, and its expression is dependent on signaling through the oncogenic NOTCH1 receptor [67]. lncRNAs HOTAIR (homeobox transcript antisense RNA) and MALAT-1 (metastasis-associated lung adenocarcinoma transcript) are associated with metastasis and recurrence [68, 69].

#### 4.2.1 lncRNA deregulation in MDS

The first study describing lncRNA in the context of MDS was published in 2010 by Benetatos et al. [70] who studied lncRNA MEG3 (maternally expressed gene 3). Abnormal methylation of its promoter was observed in a third of MDS patients and in half of AML patients [70]. MEG3 was the first lncRNA described to have a tumor suppressor function. MEG3 is expressed in many human normal tissues, and numerous studies have demonstrated that its expression level is lost in various cancers. Low expression of MEG3 is associated with an increased risk of metastasis and poor prognosis in cancer patients [71, 72].

In 2013, Yildirim et al. [73] conditionally deleted lncRNA XIST (X-inactive specific transcript) in mice hematopoietic cells. XIST is perhaps the most wellunderstood lncRNA to date. This lncRNA is located on the X chromosome and is required for X chromosome inactivation during embryogenesis. Yildirim et al. [73]

#### Noncoding RNAs in Myelodysplastic Syndromes DOI: http://dx.doi.org/10.5772/intechopen.79767

Hu et al. [63] studied the lncRNA transcriptome of the erythroid lineage and uncovered numerous erythroid-specific lncRNAs that become induced during terminal differentiation of mouse fetal liver red blood cells in vivo. These authors showed that lincRNA-EPS (erythroid prosurvival) acts to promote red blood cell maturation by downregulating proapoptotic pathways. Knockdown of lincRNA-EPS severely compromised terminal differentiation of erythroid progenitors and resulted in elevated apoptosis. Conversely, its ectopic expression protected erythroid progenitors from apoptosis triggered by erythropoietin starvation. Functional studies indicated that lincRNA-EPS acts by repressing a number of proapoptotic proteins, most prominently the caspase-activating adaptor protein

Recent studies have also provided evidence for the importance of several lncRNAs in immune cell function. For example, lncRNA NeST (Nettoie Salmonella pas Theiler's, cleanup Salmonella not Theiler's), also named Tmevpg1, modulates the ability of mice to respond to viral and bacterial infections. NeST is specifically expressed by the TH1 subset of helper T cells. The expression of NeST regulates the degree of inflammation induced by infecting pathogens, such as Thelier's virus or Salmonella [64]. lncRNA-Cox2 (cyclooxygenase 2) acts during inflammatory signaling by modulating the expression of several immune response genes via interac-

lncRNAs not only participate in normal hematopoiesis but also contribute to the pathogenesis of hematologic malignancies, representing a new class of potential biomarkers and therapeutic targets. These RNAs have significantly different expression levels in primary tumors and metastases, functioning both as oncogenes or as tumor suppressors. Some cancer-related lncRNAs could affect the development and progression of tumor by means of p53, polycomb repressive complex 2 (PRC2), and other signaling pathways. Others are not observed in normal tissue but are detected in cancer. For example, T-ALL-R-lncR1 appears to induce (together with protease-activated receptor 4 (PAR-4)) cellular apoptosis in T cell acute lymphoblastic leukemia cells (T-ALL) [66]. LUNAR1 (leukemia-induced noncoding activator RNA) is highly expressed in T-ALL cells, and its expression is dependent on signaling through the oncogenic NOTCH1 receptor [67]. lncRNAs HOTAIR (homeobox transcript antisense RNA) and MALAT-1 (metastasis-associated lung adenocarcinoma transcript) are associated with metastasis and recurrence [68, 69].

The first study describing lncRNA in the context of MDS was published in 2010 by Benetatos et al. [70] who studied lncRNA MEG3 (maternally expressed gene 3). Abnormal methylation of its promoter was observed in a third of MDS patients and in half of AML patients [70]. MEG3 was the first lncRNA described to have a tumor suppressor function. MEG3 is expressed in many human normal tissues, and numerous studies have demonstrated that its expression level is lost in various cancers. Low expression of MEG3 is associated with an increased risk of metastasis

In 2013, Yildirim et al. [73] conditionally deleted lncRNA XIST (X-inactive specific transcript) in mice hematopoietic cells. XIST is perhaps the most wellunderstood lncRNA to date. This lncRNA is located on the X chromosome and is required for X chromosome inactivation during embryogenesis. Yildirim et al. [73]

Pycard [63].

tions with regulatory complexes [65].

4.2.1 lncRNA deregulation in MDS

96

and poor prognosis in cancer patients [71, 72].

4.2 lncRNAs in malignant hematopoiesis

Recent Developments in Myelodysplastic Syndromes

demonstrated that mutant females developed a highly aggressive myeloproliferative neoplasm and MDS (mixed MPN/MDS) with 100% penetrance.

The first study examining the deregulation of lncRNAs on a genome-wide level in MDS was published in 2017 [74]. The authors combined NGS and microarray data in CD34<sup>+</sup> BM cells and identified several lncRNAs (linc-ARFIP1-4, linc-TAAR9-1, lincC2orf85, linc-RNFT2-1, and linc-RPIA) deregulated in MDS-EB2. In the same year, Yao et al. [75] profiled lncRNA expressions in 176 adult patients with primary MDS and identified four lncRNAs (TC07000551.hg.1, TC08000489.hg.1, TC02004770.hg.1, and TC03000701) with expression levels significantly associated with overall survival. Subsequently, the authors constructed a risk-scoring system with the weighted sum of these four lncRNAs. Higher lncRNA scores were associated with higher marrow blast percentages, higher-risk subtypes of MDS, complex cytogenetic changes, and mutations in RUNX1, ASXL1, TP53, SRSF2, and ZRSR2, whereas they were inversely correlated with the SF3B1 mutation. Patients with higher lncRNA scores had significantly shorter overall survival and higher 5-year leukemic transformation rate than did those with lower scores [75].

Although increasing numbers of deregulated lncRNAs are currently being described in MDS, only a few have been functionally characterized so far. Transcriptomic data may be used to construct network modules consisting of lncRNAs and protein-coding genes to enable functional analysis of lncRNAs with unknown functions. These networks are subsequently linked with annotated signaling pathways and gene ontologies. The resulting outputs provide a degree of functional annotation for differentially expressed lncRNAs in the disease and their potential roles in pathophysiology [74].

### 5. Other types of noncoding RNAs in MDS

Only very limited information regarding other groups of ncRNAs have been published for MDS to date. However, we can anticipate that introduction of nextgeneration sequencing of RNAs (so-called RNA-seq) will bring to MDS research many novel insights regarding various ncRNAs in the near future. This technology enables sensitive global detection of various RNAs across an unparalleled dynamic range. Particularly, small RNA-seq is predominantly used for detection of miRNAs. However, during library preparation, small RNAs are selected by electrophoresis with sizes typically ranging from 20 to 50 nt. This range of size selection allows for the capture of many other species of small RNAs in addition to miRNAs.

#### 5.1 Piwi-interacting RNAs

In 2011, Beck et al. [76] conducted one of the early studies to apply small RNAseq in MDS. These authors compared expression of small RNAs between low-grade (refractory anemia, RA) and high-grade (MDS-EB2) MDS patients and demonstrated the first evidence of piwi (P-element-Induced Wimpy Testis)-interacting RNAs (piRNAs) in MDS BM cells and their particular enrichment in low-grade MDS. PiRNAs are a relatively newly defined class of small ncRNAs with lengths from 26 to 32 nt. These RNAs lack sequence conservation and are more complex than miRNAs. PiRNAs have been linked to both epigenetic and posttranscriptional gene silencing of retrotransposons and other genetic elements in germline cells, particularly those involved in spermatogenesis.

Transcription of particular piwi proteins (piwil1 and piwil2) that are required for the accumulation of piRNAs was also significantly upregulated in RA [76]. Recent studies indicated that the piwi-piRNA complex may have a role in

posttranscriptional silencing of damaged DNA fragments and that interrupting piwi-piRNA formation can lead to DNA double-strand breaks [77]. In summary, the study from Beck et al. [76] suggested that the enrichment of piRNAs in low-grade MDS may potentially protect DNA from the accumulation of mutations, a mechanism not observed in high-grade MDS. Moreover, they proposed that piRNAs might be used as diagnostic markers for low-grade MDS; however, further studies of piRNA roles in MDS pathogenesis are warranted.

reduce the expression of oncogenic miRNAs or, conversely, to increase levels of miRNAs with tumor suppressor functions. Unlike targeted inhibition or activation of a single protein-coding gene, the administration of miRNA antagonists or their mimics may potentially improve the desired effects, as these molecules can regulate several genes, often in specific signaling pathways implicated in tumorigenesis. Several pharmaceutical companies already have miRNA therapeutics in their developmental pipelines [81]. In 2012, the first cancer-targeted miRNA drug, MRX34 (a liposome-based miR-34 mimic), entered phase I clinical trials in patients with advanced hepatocellular carcinoma, and this mimic has attracted considerable attention from both academic researchers and pharmaceutical companies [82]. MRG-106, a synthetic antagonist of miRNA-155, is currently being tested by MIRagen Therapeutics in patients with cutaneous T-cell lymphoma [83]. However, testing miRNAs as potential therapeutic agents or targets in MDS therapy still requires initial exploration in in vitro models before evolving to future clinical trials. Information regarding the contribution of other categories of ncRNAs, including lncRNAs, to the pathogenesis of MDS remains scarce. However, given the large number of ncRNAs encoded in the human genome and the complexity of their interactions, it can be expected that, in the near future, we will reveal a number of ncRNAs involved in MDS. It can also be anticipated that we will identify new predictive markers of progression and responses to therapy among these molecules. To conclude, the diagnostic and therapeutic possibilities of ncRNAs undoubtedly have profound potential in MDS. However, although the effects of some miRNAs have already been demonstrated, it is certain that the importance of ncRNAs in MDS will be fully understood only in the future and that many years of research and clinical trials remain before the eventual application of ncRNAs in clinical practice

This work was supported by the research grants no. 16-33617A and 17-31398A and the project for conceptual development of research organization no. 00023736

to classify, monitor, and treat this disease.

Noncoding RNAs in Myelodysplastic Syndromes DOI: http://dx.doi.org/10.5772/intechopen.79767

(all from the Ministry of Health of the Czech Republic).

The authors declare that they have no competing interests.

Acknowledgements

Conflict of interests

99

#### 5.2 Transfer RNAs

The abovementioned pioneer study from Beck et al. [76] also provided an early insight into the deregulation of tRNAs in MDS. The authors showed that ratios of tRNA to rRNA were significantly higher in MDS-EB2 compared to those of RA and controls. Because tRNAs are building blocks for protein synthesis and are required during translation, this may indicate an increased regulation of translation at this disease stage. Interestingly, a significant increase of tRNAs in tumor samples was reported by Pavon-Eternod et al. [78] In addition, tRNAs have been shown to inhibit cytochrome c-activated apoptosis [79]. Taken together, Beck et al. [76] hypothesized that high tRNA content seen in EB2 may contribute to the two wellknown characteristics of high-grade MDS, decreased apoptosis, and high rate of leukemic transformation.

Guo et al. [80] performed small RNA-seq in paired pre- and posttreatment samples from MDS patients receiving therapy with HMAs. In the sequencing data, the number of reads aligned to tRNA-derived small RNAs (tDRs) (78.81%) vastly outnumbered those aligning to miRNAs (4.43% of reads). The tRNA fragments that were captured by miRNA-seq might be a result of either active cleavage or artifacts of the miRNA-seq library construction. The authors identified six tDR fragments that were differentially expressed between MDS and normal samples. Three tDRs demonstrated increased expression in MDS (chrM.tRNA10.TC, chr12.tRNA8. AlaTGC, and chr16.tRNA4.ProAGG), while three were decreased (chr1.tRNA58- LeuCAA, chr19.tRNA8-SeC(e)TCA (SeC(e)TCA), and chr19.tRNA4-ThrAGT). Moreover, they identified a panel of four tRNA fragments (chr6.tRNA157.ValCAC, chr11.tRNA17.ValTAC, chrM.tRNA12.TS1, and chrX.tRNA4.ValTAC), whose combined expression in the pretreatment samples together was predictive of the likelihood of response. Deeper focus on mitochondrial tRNAs revealed that MT-TS1 (mitochondrially encoded tRNA serine 1) was the only mitochondrial tRNA to have a significant association with treatment response [80].

#### 6. Conclusions

The discovery of ncRNAs has initiated a new era in molecular biology, completely changing our view of "junk" DNA that it is no longer considered unnecessary ballast. Mouse models have clearly demonstrated key functions of ncRNAs in regulatory networks and their ability to significantly influence biological processes. In the hematopoietic system, ncRNAs represent important regulators of HSC "stemness" and differentiation; therefore, it is not surprising that deregulation of ncRNAs also occurs in MDS.

Currently, we possess comprehensive information regarding the impact of miRNA deregulation on the pathogenesis of MDS. The efforts of current research activities aim to apply these findings to clinical practice, testing the potential diagnostic/prognostic value of selected miRNAs for MDS. However, miRNAs also represent promising therapeutic agents or targets. miRNA-based drugs are designed to Noncoding RNAs in Myelodysplastic Syndromes DOI: http://dx.doi.org/10.5772/intechopen.79767

posttranscriptional silencing of damaged DNA fragments and that interrupting piwi-piRNA formation can lead to DNA double-strand breaks [77]. In summary, the study from Beck et al. [76] suggested that the enrichment of piRNAs in low-grade MDS may potentially protect DNA from the accumulation of mutations, a mechanism not observed in high-grade MDS. Moreover, they proposed that piRNAs might be used as diagnostic markers for low-grade MDS; however, further studies of

The abovementioned pioneer study from Beck et al. [76] also provided an early insight into the deregulation of tRNAs in MDS. The authors showed that ratios of tRNA to rRNA were significantly higher in MDS-EB2 compared to those of RA and controls. Because tRNAs are building blocks for protein synthesis and are required during translation, this may indicate an increased regulation of translation at this disease stage. Interestingly, a significant increase of tRNAs in tumor samples was reported by Pavon-Eternod et al. [78] In addition, tRNAs have been shown to inhibit cytochrome c-activated apoptosis [79]. Taken together, Beck et al. [76] hypothesized that high tRNA content seen in EB2 may contribute to the two wellknown characteristics of high-grade MDS, decreased apoptosis, and high rate of

Guo et al. [80] performed small RNA-seq in paired pre- and posttreatment samples from MDS patients receiving therapy with HMAs. In the sequencing data, the number of reads aligned to tRNA-derived small RNAs (tDRs) (78.81%) vastly outnumbered those aligning to miRNAs (4.43% of reads). The tRNA fragments that were captured by miRNA-seq might be a result of either active cleavage or artifacts of the miRNA-seq library construction. The authors identified six tDR fragments that were differentially expressed between MDS and normal samples. Three tDRs demonstrated increased expression in MDS (chrM.tRNA10.TC, chr12.tRNA8. AlaTGC, and chr16.tRNA4.ProAGG), while three were decreased (chr1.tRNA58- LeuCAA, chr19.tRNA8-SeC(e)TCA (SeC(e)TCA), and chr19.tRNA4-ThrAGT). Moreover, they identified a panel of four tRNA fragments (chr6.tRNA157.ValCAC, chr11.tRNA17.ValTAC, chrM.tRNA12.TS1, and chrX.tRNA4.ValTAC), whose combined expression in the pretreatment samples together was predictive of the likelihood of response. Deeper focus on mitochondrial tRNAs revealed that MT-TS1 (mitochondrially encoded tRNA serine 1) was the only mitochondrial tRNA to have

The discovery of ncRNAs has initiated a new era in molecular biology, completely changing our view of "junk" DNA that it is no longer considered unnecessary ballast. Mouse models have clearly demonstrated key functions of ncRNAs in regulatory networks and their ability to significantly influence biological processes. In the hematopoietic system, ncRNAs represent important regulators of HSC "stemness" and differentiation; therefore, it is not surprising that deregulation

Currently, we possess comprehensive information regarding the impact of miRNA deregulation on the pathogenesis of MDS. The efforts of current research activities aim to apply these findings to clinical practice, testing the potential diagnostic/prognostic value of selected miRNAs for MDS. However, miRNAs also represent promising therapeutic agents or targets. miRNA-based drugs are designed to

piRNA roles in MDS pathogenesis are warranted.

Recent Developments in Myelodysplastic Syndromes

a significant association with treatment response [80].

5.2 Transfer RNAs

leukemic transformation.

6. Conclusions

98

of ncRNAs also occurs in MDS.

reduce the expression of oncogenic miRNAs or, conversely, to increase levels of miRNAs with tumor suppressor functions. Unlike targeted inhibition or activation of a single protein-coding gene, the administration of miRNA antagonists or their mimics may potentially improve the desired effects, as these molecules can regulate several genes, often in specific signaling pathways implicated in tumorigenesis. Several pharmaceutical companies already have miRNA therapeutics in their developmental pipelines [81]. In 2012, the first cancer-targeted miRNA drug, MRX34 (a liposome-based miR-34 mimic), entered phase I clinical trials in patients with advanced hepatocellular carcinoma, and this mimic has attracted considerable attention from both academic researchers and pharmaceutical companies [82]. MRG-106, a synthetic antagonist of miRNA-155, is currently being tested by MIRagen Therapeutics in patients with cutaneous T-cell lymphoma [83]. However, testing miRNAs as potential therapeutic agents or targets in MDS therapy still requires initial exploration in in vitro models before evolving to future clinical trials.

Information regarding the contribution of other categories of ncRNAs, including lncRNAs, to the pathogenesis of MDS remains scarce. However, given the large number of ncRNAs encoded in the human genome and the complexity of their interactions, it can be expected that, in the near future, we will reveal a number of ncRNAs involved in MDS. It can also be anticipated that we will identify new predictive markers of progression and responses to therapy among these molecules.

To conclude, the diagnostic and therapeutic possibilities of ncRNAs undoubtedly have profound potential in MDS. However, although the effects of some miRNAs have already been demonstrated, it is certain that the importance of ncRNAs in MDS will be fully understood only in the future and that many years of research and clinical trials remain before the eventual application of ncRNAs in clinical practice to classify, monitor, and treat this disease.

#### Acknowledgements

This work was supported by the research grants no. 16-33617A and 17-31398A and the project for conceptual development of research organization no. 00023736 (all from the Ministry of Health of the Czech Republic).

#### Conflict of interests

The authors declare that they have no competing interests.

Recent Developments in Myelodysplastic Syndromes

## Author details

Andrea Hruštincová†, Katarina Szikszai†, Zdeněk Krejčík, Nikoleta Loudová and Michaela Dostálová Merkerová\* Department of Genomics, Institute of Hematology and Blood Transfusion, Prague, Czech Republic

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Noncoding RNAs in Myelodysplastic Syndromes DOI: http://dx.doi.org/10.5772/intechopen.79767

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\*Address all correspondence to: michaela.merkerova@uhkt.cz

† These authors contributed equally to this work.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Noncoding RNAs in Myelodysplastic Syndromes DOI: http://dx.doi.org/10.5772/intechopen.79767

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[16] Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834- 838. DOI: 10.1038/nature03702

Author details

Czech Republic

†

100

Michaela Dostálová Merkerová\*

Recent Developments in Myelodysplastic Syndromes

Andrea Hruštincová†, Katarina Szikszai†, Zdeněk Krejčík, Nikoleta Loudová and

\*Address all correspondence to: michaela.merkerova@uhkt.cz

These authors contributed equally to this work.

provided the original work is properly cited.

Department of Genomics, Institute of Hematology and Blood Transfusion, Prague,

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

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Recent Developments in Myelodysplastic Syndromes

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Mendell J, Prchal JT. Regulated

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Proceedings of the National Academy of

pone.0075815

differentiation of human acute leukemia

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Proceedings of the National Academy of

[20] Diehl P, Fricke A, Sander L, Stamm

Microparticles: Major transport vehicles for distinct microRNAs in circulation. Cardiovascular Research. 2012;93:633-

[21] Chen CZ, Li L, Lodish HF, Bartel

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[83] Foss FM, Querfeld C, Porcu P, Kim YH, Pacheco T, Halwani AS. Phase 1 trial evaluating MRG-106, a synthetic inhibitor of microRNA-155, in patients with cutaneous t-cell lymphoma (CTCL). Journal of Clinical Oncology. 2017;35(15\_suppl):7564-7564. DOI: 10.1200/JCO.2017.35.15\_suppl.7564

## *Edited by Ota Fuchs*

This book deals with the rapid progress in the area of myelodysplastic syndromes (MDS). MDS are a group of age-associated heterogeneous malignant bone marrow stem cell disorders. MDS are characterized by ineffective hematopoiesis, which leads to refractory cytopenias and to clonal instability. Patients with MDS have myeloid dysplasia, intramedullary apoptosis and an increased risk of transformation to acute myeloid leukemia (AML). The use of next generation sequencing has allowed for the identification of molecular mutations in several genes in about 90% of MDS patients. Several mutations will likely be incorporated into future prognostic scoring systems for MDS. About 50% of MDS cases are characterized by the presence of cytogenetic abnormalities. The correct morphological and cytogenetic analysis interpretation plays an important role in diagnosis and prognosis of these disorders. Cell death and an inflammatory gene signature are associated with MDS. Better understanding of the genetic and molecular mechanisms of MDS pathogenesis provides an opportunity for new treatment strategies to be developed. Promising novel therapies targeting pathophysiological mechanisms of MDS are being studied but the drugs currently used in MDS therapy remain limited. The only curative therapy for MDS is allogeneic hematopoietic stem cell transplantation. Recent advances in strategies to minimize transplant-related toxicity make this treatment possible for more MDS patients who are sufficiently fit.

Published in London, UK © 2019 IntechOpen © xrender / iStock

Recent Developments in Myelodysplastic Syndromes

Recent Developments in

Myelodysplastic Syndromes

*Edited by Ota Fuchs*