Preface

Genome and exome sequencing together with targeted deep-sequencing studies have defined several gene mutations in almost every myelodysplastic syndrome (MDS) patient. These mutations can impact disease phenotype, prognosis and disease progression. However, there are many non-pathogenic mutations, and most mutations are not specific for MDS. Applying this information clinically is in progress even if the clinical impact of some mutations remains controversial. Several mutations will likely be incorporated into future prognostic scoring systems. Great progress has also been reached in the studies of non-coding RNAs in MDS. It is possible that they will be used in MDS diagnostics and prognosis. Big advancements in the studies of immune mechanisms in MDS have been achieved and translated into clinical studies of immunotherapies in MDS. Innate and adaptive immune pathways are excessively active in the niche of hematopoietic cells in MDS. Common etiological mechanisms of MDS and autoimmune diseases is possible because these diseases are often associated with MDS. Unfortunately, no new drugs have been approved for MDS since approval by the Food and Drug Administration of azacitidine in 2004, lenalidomide in 2005, and decitabine in 2006. The European Medicines Agency approved azacitidine in 2008 and lenalidomide in 2013. This progress in many aspects of MDS warrants this new book about this heterogeneous group of clonal neoplasms arising from hematopoietic stem cells, and characterized by inefficient hematopoiesis, peripheral cytopenias, frequent karyotypic abnormalities, risk of clonal evolution, and transformation to acute myeloid leukemia, three years after the last book about MDS published by IntechOpen.

This book provides a review of several fields of MDS not only for research workers and clinicians, but also for medical students with an interest in MDS. The first introductory chapter deals with recent progress in this area. The second chapter provides a review of diagnosis and classification of MDS. Chapter 3 discusses the association of MDS and autoimmune disorders. Chapter 4 introduces immune dysregulation in MDS. The fifth chapter analyzes an update on pathophysiology and management of MDS. The last chapter discusses non-coding RNAs in MDS.

> **Ota Fuchs, PhD** Institute of Hematology and Blood Transfusion, Department of Genomics, Prague, Czech Republic

**1**

**Chapter 1**

*Ota Fuchs*

**gene mutations**

trisomy 8 or trisomy 21 [7].

complex) [4, 8–10].

often controversial.

Introductory Chapter: Progress in

Myelodysplastic Syndrome Area

**1. Advances in our knowledge of cytogenetic abnormalities and**

Myelodysplastic syndromes (MDS) constitute a group of age-associated heterogeneous clonal hematopoietic disorders characterized by ineffective hematopoiesis with peripheral cytopenias, dysplasia, and an increased risk of progression to acute myeloid leukemia (AML) [1–6]. About 50% of cases of MDS are characterized by the presence of cytogenetic abnormalities. Losses of chromosomal material as del(5q), del(20q), monosomy 7 or del(7q), and del(Y) are most common cytogenetic abnormalities and are more frequent than gains of chromosomal material as

MDS are caused by abnormalities in many genes. The great progress in analysis of these mutations and in elucidation of relationships between gene mutations and clinical phenotypes of these disorders was achieved. Somatic mutations were found in more than 90%. Next-generation sequencing (NGS) detected about 10 different mutations in almost every patient with MDS. The majority of these mutations are nonpathogenic passenger mutations. However, one or more driver mutations in most patients with MDS are associated with the pathogenesis of MDS. Gene mutations affect proteins involved in various important cell processes as RNA-splicing, DNA methylation, histone and chromatin modifications, signal transduction, transcription (transcription factors), tumor suppressor (*TP53*), *RAS* pathway, and separation of sister chromatids during cell division (cohesion

RNA-splicing and DNA methylation mutations occur early and are known as founding mutations. Other mutations are called subclonal mutations. No MDSspecific mutations exist. Strongly represented mutations in genes coding for proteins involved in DNA methylation, such as *TET2*, *DNMT3A*, and *ASXL1*, are common also in older individuals with normal blood count (clonal hematopoiesis of indeterminate potential/CHIP/) [11, 12]. Until now, mutations in *TP53*, *EZH2*, *RUNX1*, and *SF3B1* predict independently overall survival (OS) of MDS patients. The first three mutations are associated with shorter OS but the last mutation is connected with better survival in refractory anemia with ring sideroblast (MDS-RS) and with thrombocytosis (RARS-T) [13, 14]. *SF3B1* mutations are present in about 80% of MDS-RS and correlates with its development. *SF3B1* mutations could alter the expression of the gene for ABCB7 transporter and abnormally regulate iron homeostasis in mitochondria mediating the phenotype of acquired MDS-RS [15]. Effects of other mutations are not clear up to now and results are

We lack clinical methods to stop clonal development from relatively benign state of CHIP to malignancy. Especially, *TP53*-mutant clones induce progress to therapyrelated MDS/AML. Therapy-related myeloid neoplasms have mutations in *TP53* and

### **Chapter 1**

## Introductory Chapter: Progress in Myelodysplastic Syndrome Area

*Ota Fuchs*

### **1. Advances in our knowledge of cytogenetic abnormalities and gene mutations**

Myelodysplastic syndromes (MDS) constitute a group of age-associated heterogeneous clonal hematopoietic disorders characterized by ineffective hematopoiesis with peripheral cytopenias, dysplasia, and an increased risk of progression to acute myeloid leukemia (AML) [1–6]. About 50% of cases of MDS are characterized by the presence of cytogenetic abnormalities. Losses of chromosomal material as del(5q), del(20q), monosomy 7 or del(7q), and del(Y) are most common cytogenetic abnormalities and are more frequent than gains of chromosomal material as trisomy 8 or trisomy 21 [7].

MDS are caused by abnormalities in many genes. The great progress in analysis of these mutations and in elucidation of relationships between gene mutations and clinical phenotypes of these disorders was achieved. Somatic mutations were found in more than 90%. Next-generation sequencing (NGS) detected about 10 different mutations in almost every patient with MDS. The majority of these mutations are nonpathogenic passenger mutations. However, one or more driver mutations in most patients with MDS are associated with the pathogenesis of MDS. Gene mutations affect proteins involved in various important cell processes as RNA-splicing, DNA methylation, histone and chromatin modifications, signal transduction, transcription (transcription factors), tumor suppressor (*TP53*), *RAS* pathway, and separation of sister chromatids during cell division (cohesion complex) [4, 8–10].

RNA-splicing and DNA methylation mutations occur early and are known as founding mutations. Other mutations are called subclonal mutations. No MDSspecific mutations exist. Strongly represented mutations in genes coding for proteins involved in DNA methylation, such as *TET2*, *DNMT3A*, and *ASXL1*, are common also in older individuals with normal blood count (clonal hematopoiesis of indeterminate potential/CHIP/) [11, 12]. Until now, mutations in *TP53*, *EZH2*, *RUNX1*, and *SF3B1* predict independently overall survival (OS) of MDS patients. The first three mutations are associated with shorter OS but the last mutation is connected with better survival in refractory anemia with ring sideroblast (MDS-RS) and with thrombocytosis (RARS-T) [13, 14]. *SF3B1* mutations are present in about 80% of MDS-RS and correlates with its development. *SF3B1* mutations could alter the expression of the gene for ABCB7 transporter and abnormally regulate iron homeostasis in mitochondria mediating the phenotype of acquired MDS-RS [15]. Effects of other mutations are not clear up to now and results are often controversial.

We lack clinical methods to stop clonal development from relatively benign state of CHIP to malignancy. Especially, *TP53*-mutant clones induce progress to therapyrelated MDS/AML. Therapy-related myeloid neoplasms have mutations in *TP53* and epigenetic modifying genes, instead of mutations in tyrosine kinase and spliceosome genes [16]. The possible treatments are now the use of hypomethylating agents or in future anti-inflammatory therapy and clonally selective immunotherapies.

MDS are associated with genomic instability and extensive DNA damage caused by deficient repair mechanisms. Aberrations in DNA damage response/repair genes other than *TP53* and some genes involved in DNA damage checkpoints are rare. Differential expression of homologous recombination DNA repair-associated genes during MDS progression was detected and could be confirmed as new biomarkers related to pathogenesis and poor prognosis in MDS [17, 18].

### **2. Advance in our understanding of del(5q) myelodysplastic syndrome pathogenesis and its treatment with lenalidomide**

The greatest progress was achieved in the study of molecular pathogenesis of del(5q) MDS disease phenotype and its treatment by immunomodulatory or cereblon-binding drug lenalidomide [2, 19–35]. Ebert et al. described that impaired ribosome biosynthesis due to *RPS14* (ribosomal protein 14 of the small ribosome subunit) gene haploinsufficiency leads to the E3 ubiquitin ligase HDM2 (human homolog to mouse double minute 2, major negative regulator of p53) inactivation by free ribosomal proteins, particularly RPL11 [36]. HDM2 degradation drives p53-mediated apoptosis of erythroid cells carrying the del(5q) aberration. This p53-mediated apoptosis of erythroid cells is a key effector of hypoplastic anemia in MDS patients with del(5q) [36]. *RPS14* haploinsufficiency causes a block in erythroid differentiation mediated by calprotectin (the heterodimeric S100 calciumbinding proteins S100A8 and S100A9) [37]. Proinflammatory proteins, S100A9 and tumor necrosis factor-α, suppress the effect of erythropoietin in MDS [38]. Some patients originally considered as MDS patients without del(5q) can have a phenotype of atypical 5q− syndrome and can be sensitive to lenalidomide therapy because they have diminutive somatic deletions in the 5q region. These deletions were not identified by fluorescence in situ hybridization or cytogenetic testing but by single nucleotide polymorphism array genotyping [39]. Low RPS14 expression in 50–70% MDS patients without del(5q) confers higher apoptosis rate of nucleated erythrocytes and predicts prolonged survival [40, 41].

What is the mechanism of lenalidomide in del(5q) MDS based on what has been achieved and elucidated to date? Lenalidomide stabilizes E3 ubiquitin ligase HDM2, thereby accelerating p53 degradation [42, 43]. Lenalidomide inhibits phosphatases PP2a and Cdc25c (coregulators of cell cycle which genes are very commonly deleted in del(5q) MDS) with consequent G2 arrest of del(5q) MDS progenitors and their apoptosis. PP2a and Cdc25c inhibition by lenalidomide suppress HDM2 autoubiquitination and subsequent degradation. Thus, lenalidomide has been shown to not only reverse apoptosis within the erythroid compartment, but also directly induce apoptosis of the myeloid clone in del(5q) MDS [44, 45]. Lenalidomide upregulates expression of other two haploinsufficient genes located on chromosome 5q, genes for microRNAs (miR-145 and miR-146a) [46]. These miRs are involved in Toll-like receptor pathway, IL-6 induction, and regulation of megakaryopoiesis [20].

Ito et al. discovered that thalidomide (founding member of immunomodulatory drugs/IMiDs/) binds cereblon (CRBN) in the terminal C-region (parts of exons 10 and 11 of the *CRBN* gene code this IMiD binding region) [47]. Several researchers confirmed CRBN as target of lenalidomide in multiple myeloma (MM), lymphoma, chronic lymphocytic leukemia, and del(5q) MDS [48]. CRBN is the ubiquitously expressed 51 kDa protein with a putative role in cerebral development, especially memory and learning [49, 50].

**3**

*Introductory Chapter: Progress in Myelodysplastic Syndrome Area*

subgroup known to be especially sensitive to lenalidomide [51].

mutations on lenalidomide treatment in del(5q) MDS [57, 58].

of GATA2 transcriptional complex [59].

**treatment and new possible therapies**

Even if the treatment of del(5q) MDS patients with lenalidomide is very efficient, 50% of treated patients relapse after 2–3 years. Martinez-Hoyer et al. found that low platelet count and occurrence of additional mutations, mainly *TP53* mutations induce lenalidomide resistance [59–61]. They used whole genome sequencing and observed in several resistant patients mutations in *RUNX1* gene or decreased amount of *RUNX1* transcript without aberration in *TP53* [59]. Results were verified in model system of two human del(5q) lines, MDS-L and KG-1a. *RUNX1* knock-out or RUNX1 shRNA increased proliferation and reduced apoptosis in lenalidomidetreated cells with decreased *RUNX1* transcript. Therefore, effect of lenalidomide in del(5q) requires functional RUNX1. Similar results were obtained with *TP53* knock-out cells. Both *RUNX1* and *TP53* transcripts cooperate and alter the activity

**3. Studies on lenalidomide use also in lower risk non-del(5q) MDS** 

While CSNK1A1 is CRL4CRBN target in del(5q) MDS, CRL4CRBN targets in lower risk non-del(5q) remain to be determined. The mechanism of action of lenalidomide is still unclear in non-del(5q) MDS cells. Recent evidence shows that lenalidomide directly improves erythropoietin receptor (EPOR) signaling by EPOR upregulation mediated by a posttranscriptional mechanism [62]. Lenalidomide

Our group found that del(5q) MDS patients (the so-called 5q minus syndrome) have higher levels of full-length CRBN mRNA than other patients with lower risk MDS, linking higher levels of a known lenalidomide target CRBN and del(5q) MDS

CRBN is a member and substrate receptor of the cullin 4 RING E3 ubiquitin ligase complex (CRL4). CRBN recruits substrate proteins to the CRL4 complex for ubiquitination and the subsequent degradation in proteasomes. IMiDs binds to CRBN in CRL4 complex and block normal endogenous substrates (CRBN and the homeobox transcription factor MEIS2 in multiple myeloma/MM/) from binding to CRL4 for ubiquitination and degradation [52]. After IMID binding to CRBN, CRL4 complex is recruiting transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) for ubiquitination and degradation in MM cells [53]. Degradation of these transcription factors explains lenalidomide's growth inhibition of MM cells and increased interleukin-2 (IL-2) release from T cells. However, it is unlikely that degradation of IKZF1 and IKZF3 accounts for lenalidomide's activity in MDS with del(5q). Fink et al. identified a novel target casein kinase1A1 (CSNK1A1) by quantitative proteomics in the myeloid cell line KG-1 [54]. CSNK1A1 is encoded in the del(5q) commonly deleted region and the gene is haploinsufficient. Lenalidomide treatment leads to increased ubiquitination of the remaining CSNK1A1 and decreased protein abundance. CSNK1A1 negatively regulates β-catenin which drives stem cell self-renewal, and *CSNK1A1* haploinsufficiency causes the initial clonal expansion in patients with the del(5q) MDS and contributes to the pathogenesis of del(5q) MDS. The further inhibition of CSNK1A1 in del(5q) MDS is associated with del(5q) failure and p53 activation. The inhibition of CSNK1A1 reduced RPS6 phosphorylation, induced p53 expression and growth inhibition, and triggered myeloid differentiation program. TP53-null leukemia did not respond to CSNK1A1 inhibition, strongly supporting the importance of the p53 expression for the yield of CSNK1A1 inhibition. *CSNK1A1* mutations have been recently found in 5–18% of MDS patients with del(5q) [55]. These mutations are associated similarly to the effect of *TP53* mutations with rise to a poor prognosis in del(5q) MDS [56]. Other studies did not find impact of *CSNK1A1*

*DOI: http://dx.doi.org/10.5772/intechopen.84594*

#### *Introductory Chapter: Progress in Myelodysplastic Syndrome Area DOI: http://dx.doi.org/10.5772/intechopen.84594*

*Recent Developments in Myelodysplastic Syndromes*

related to pathogenesis and poor prognosis in MDS [17, 18].

**pathogenesis and its treatment with lenalidomide**

cytes and predicts prolonged survival [40, 41].

epigenetic modifying genes, instead of mutations in tyrosine kinase and spliceosome genes [16]. The possible treatments are now the use of hypomethylating agents or in future anti-inflammatory therapy and clonally selective immunotherapies.

MDS are associated with genomic instability and extensive DNA damage caused by deficient repair mechanisms. Aberrations in DNA damage response/repair genes other than *TP53* and some genes involved in DNA damage checkpoints are rare. Differential expression of homologous recombination DNA repair-associated genes during MDS progression was detected and could be confirmed as new biomarkers

**2. Advance in our understanding of del(5q) myelodysplastic syndrome** 

The greatest progress was achieved in the study of molecular pathogenesis of del(5q) MDS disease phenotype and its treatment by immunomodulatory or cereblon-binding drug lenalidomide [2, 19–35]. Ebert et al. described that impaired ribosome biosynthesis due to *RPS14* (ribosomal protein 14 of the small ribosome subunit) gene haploinsufficiency leads to the E3 ubiquitin ligase HDM2 (human homolog to mouse double minute 2, major negative regulator of p53) inactivation by free ribosomal proteins, particularly RPL11 [36]. HDM2 degradation drives p53-mediated apoptosis of erythroid cells carrying the del(5q) aberration. This p53-mediated apoptosis of erythroid cells is a key effector of hypoplastic anemia in MDS patients with del(5q) [36]. *RPS14* haploinsufficiency causes a block in erythroid differentiation mediated by calprotectin (the heterodimeric S100 calciumbinding proteins S100A8 and S100A9) [37]. Proinflammatory proteins, S100A9 and tumor necrosis factor-α, suppress the effect of erythropoietin in MDS [38]. Some patients originally considered as MDS patients without del(5q) can have a phenotype of atypical 5q− syndrome and can be sensitive to lenalidomide therapy because they have diminutive somatic deletions in the 5q region. These deletions were not identified by fluorescence in situ hybridization or cytogenetic testing but by single nucleotide polymorphism array genotyping [39]. Low RPS14 expression in 50–70% MDS patients without del(5q) confers higher apoptosis rate of nucleated erythro-

What is the mechanism of lenalidomide in del(5q) MDS based on what has been achieved and elucidated to date? Lenalidomide stabilizes E3 ubiquitin ligase HDM2, thereby accelerating p53 degradation [42, 43]. Lenalidomide inhibits phosphatases PP2a and Cdc25c (coregulators of cell cycle which genes are very commonly deleted in del(5q) MDS) with consequent G2 arrest of del(5q) MDS progenitors and their apoptosis. PP2a and Cdc25c inhibition by lenalidomide suppress HDM2 autoubiquitination and subsequent degradation. Thus, lenalidomide has been shown to not only reverse apoptosis within the erythroid compartment, but also directly induce apoptosis of the myeloid clone in del(5q) MDS [44, 45]. Lenalidomide upregulates expression of other two haploinsufficient genes located on chromosome 5q, genes for microRNAs (miR-145 and miR-146a) [46]. These miRs are involved in Toll-like receptor pathway, IL-6 induction, and regulation of megakaryopoiesis [20].

Ito et al. discovered that thalidomide (founding member of immunomodulatory drugs/IMiDs/) binds cereblon (CRBN) in the terminal C-region (parts of exons 10 and 11 of the *CRBN* gene code this IMiD binding region) [47]. Several researchers confirmed CRBN as target of lenalidomide in multiple myeloma (MM), lymphoma, chronic lymphocytic leukemia, and del(5q) MDS [48]. CRBN is the ubiquitously expressed 51 kDa protein with a putative role in cerebral development, especially

**2**

memory and learning [49, 50].

Our group found that del(5q) MDS patients (the so-called 5q minus syndrome) have higher levels of full-length CRBN mRNA than other patients with lower risk MDS, linking higher levels of a known lenalidomide target CRBN and del(5q) MDS subgroup known to be especially sensitive to lenalidomide [51].

CRBN is a member and substrate receptor of the cullin 4 RING E3 ubiquitin ligase complex (CRL4). CRBN recruits substrate proteins to the CRL4 complex for ubiquitination and the subsequent degradation in proteasomes. IMiDs binds to CRBN in CRL4 complex and block normal endogenous substrates (CRBN and the homeobox transcription factor MEIS2 in multiple myeloma/MM/) from binding to CRL4 for ubiquitination and degradation [52]. After IMID binding to CRBN, CRL4 complex is recruiting transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) for ubiquitination and degradation in MM cells [53]. Degradation of these transcription factors explains lenalidomide's growth inhibition of MM cells and increased interleukin-2 (IL-2) release from T cells. However, it is unlikely that degradation of IKZF1 and IKZF3 accounts for lenalidomide's activity in MDS with del(5q). Fink et al. identified a novel target casein kinase1A1 (CSNK1A1) by quantitative proteomics in the myeloid cell line KG-1 [54]. CSNK1A1 is encoded in the del(5q) commonly deleted region and the gene is haploinsufficient. Lenalidomide treatment leads to increased ubiquitination of the remaining CSNK1A1 and decreased protein abundance. CSNK1A1 negatively regulates β-catenin which drives stem cell self-renewal, and *CSNK1A1* haploinsufficiency causes the initial clonal expansion in patients with the del(5q) MDS and contributes to the pathogenesis of del(5q) MDS. The further inhibition of CSNK1A1 in del(5q) MDS is associated with del(5q) failure and p53 activation. The inhibition of CSNK1A1 reduced RPS6 phosphorylation, induced p53 expression and growth inhibition, and triggered myeloid differentiation program. TP53-null leukemia did not respond to CSNK1A1 inhibition, strongly supporting the importance of the p53 expression for the yield of CSNK1A1 inhibition. *CSNK1A1* mutations have been recently found in 5–18% of MDS patients with del(5q) [55]. These mutations are associated similarly to the effect of *TP53* mutations with rise to a poor prognosis in del(5q) MDS [56]. Other studies did not find impact of *CSNK1A1* mutations on lenalidomide treatment in del(5q) MDS [57, 58].

Even if the treatment of del(5q) MDS patients with lenalidomide is very efficient, 50% of treated patients relapse after 2–3 years. Martinez-Hoyer et al. found that low platelet count and occurrence of additional mutations, mainly *TP53* mutations induce lenalidomide resistance [59–61]. They used whole genome sequencing and observed in several resistant patients mutations in *RUNX1* gene or decreased amount of *RUNX1* transcript without aberration in *TP53* [59]. Results were verified in model system of two human del(5q) lines, MDS-L and KG-1a. *RUNX1* knock-out or RUNX1 shRNA increased proliferation and reduced apoptosis in lenalidomidetreated cells with decreased *RUNX1* transcript. Therefore, effect of lenalidomide in del(5q) requires functional RUNX1. Similar results were obtained with *TP53* knock-out cells. Both *RUNX1* and *TP53* transcripts cooperate and alter the activity of GATA2 transcriptional complex [59].

### **3. Studies on lenalidomide use also in lower risk non-del(5q) MDS treatment and new possible therapies**

While CSNK1A1 is CRL4CRBN target in del(5q) MDS, CRL4CRBN targets in lower risk non-del(5q) remain to be determined. The mechanism of action of lenalidomide is still unclear in non-del(5q) MDS cells. Recent evidence shows that lenalidomide directly improves erythropoietin receptor (EPOR) signaling by EPOR upregulation mediated by a posttranscriptional mechanism [62]. Lenalidomide

stabilizes the EPOR protein by inhibition of the E3 ubiquitin ligase RNF41 (ring finger protein 41, also known as neuregulin receptor degradation protein-1/Nrdp1/ and fetal liver ring finger/FLRF/) responsible for EPOR polyubiquitination and next degradation [62] and induces lipid raft assembly to enhance EPOR signaling in MDS erythroid progenitors [63, 64].

After failure of ESAs, lenalidomide yields red blood cell transfusion independence in 20–30% of lower risk non-del(5q) MDS. Indeed, several observations suggest an additive effect of ESA and lenalidomide in this situation [65, 66] and also in del(5q) MDS patients [67]. Synthetic corticosteroids (dexamethasone and prednisone) are also able to potentiate the effect of lenalidomide or combination of lenalidomide and erythropoietin [67–69].

Basiorka et al. and Sallman et al. reported activation of the NLRP3 inflammasome in MDS [70, 71]. NRLP3 drives clonal expansion and pyroptotic cell death. Independent of genotype, MDS hematopoietic stem and progenitor cells (HSPCs) overexpress inflammasome proteins. Activated NLRP3 complexes direct then activation of caspase-1, generation of interleukin-1β (IL-1β) and IL-18, and pyroptotic cell death. Mechanistically, pyroptosis is triggered by the alarmin S100A9 that is found in excess in MDS HSPCs and bone marrow plasma. Further, like somatic gene mutations, S100A9-induced signaling activates NADPH oxidase (NOX) and increasing levels of reactive oxygen species (ROS). ROS initiate cation influx, cell swelling, and β-catenin activation. Knockdown of NLRP3 or caspase-1, neutralization of S100A9, and pharmacologic inhibition of NLRP3 or NOX suppress pyroptosis, ROS generation, and nuclear β-catenin in MDSs and are sufficient to restore effective hematopoiesis. Thus, alarmins and founder gene mutations in MDSs cause a common redox-sensitive inflammasome circuit. They are new candidates for therapeutic intervention.

Not only apoptosis and pyroptosis are involved in increased cell death in MDS. Recently, possible further mechanism of cell death, necroptosis, in MDS has been described [72, 73]. Necroptosis is like pyroptosis associated with membrane permeabilization and the release of damage-associated molecular patterns (DAMPs) such as alarmins. Alarmins bind Toll-like receptor 4 (TLR4) and activate the transcription factor NF-κB and inflammation [74].

The effects of lenalidomide in non-del(5q) are thought to be secondary to modulation of the immune system. Hyperactivated T cells inhibit hematopoiesis. Immunosuppressive therapies with antithymocyte globulin alone and in combination with prednisone or cyclosporine show response rates between 25 and 40% [75, 76].

The studies discussed in this and other chapters of this book will help to translate our knowledge of genetic aberrations and of pathophysiological mechanisms in MDS into clinical use in diagnosis, prognosis, and therapy. Novel agents developed on the basis of this knowledge (luspatercept, rigosertib, immune checkpoint inhibitors, venetoclax, and others) are in clinical trials and will help in relapsed/ refractory MDS.

The work of our group in this area was supported by the research project for conceptual development of research organization (00023736; Institute of Hematology and Blood Transfusion, Prague) from the Ministry of Health of the Czech Republic.

**5**

**Author details**

Ota Fuchs

provided the original work is properly cited.

\*Address all correspondence to: ota.fuchs@uhkt.cz

*Introductory Chapter: Progress in Myelodysplastic Syndrome Area*

*DOI: http://dx.doi.org/10.5772/intechopen.84594*

© 2019 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,

Institute of Hematology and Blood Transfusion, Prague, Czech Republic

*Introductory Chapter: Progress in Myelodysplastic Syndrome Area DOI: http://dx.doi.org/10.5772/intechopen.84594*

*Recent Developments in Myelodysplastic Syndromes*

MDS erythroid progenitors [63, 64].

lenalidomide and erythropoietin [67–69].

therapeutic intervention.

refractory MDS.

Czech Republic.

stabilizes the EPOR protein by inhibition of the E3 ubiquitin ligase RNF41 (ring finger protein 41, also known as neuregulin receptor degradation protein-1/Nrdp1/ and fetal liver ring finger/FLRF/) responsible for EPOR polyubiquitination and next degradation [62] and induces lipid raft assembly to enhance EPOR signaling in

After failure of ESAs, lenalidomide yields red blood cell transfusion independence in 20–30% of lower risk non-del(5q) MDS. Indeed, several observations suggest an additive effect of ESA and lenalidomide in this situation [65, 66] and also in del(5q) MDS patients [67]. Synthetic corticosteroids (dexamethasone and prednisone) are also able to potentiate the effect of lenalidomide or combination of

Basiorka et al. and Sallman et al. reported activation of the NLRP3 inflammasome in MDS [70, 71]. NRLP3 drives clonal expansion and pyroptotic cell death. Independent of genotype, MDS hematopoietic stem and progenitor cells (HSPCs) overexpress inflammasome proteins. Activated NLRP3 complexes direct then activation of caspase-1, generation of interleukin-1β (IL-1β) and IL-18, and pyroptotic cell death. Mechanistically, pyroptosis is triggered by the alarmin S100A9 that is found in excess in MDS HSPCs and bone marrow plasma. Further, like somatic gene mutations, S100A9-induced signaling activates NADPH oxidase (NOX) and increasing levels of reactive oxygen species (ROS). ROS initiate cation influx, cell swelling, and β-catenin activation. Knockdown of NLRP3 or caspase-1, neutralization of S100A9, and pharmacologic inhibition of NLRP3 or NOX suppress pyroptosis, ROS generation, and nuclear β-catenin in MDSs and are sufficient to restore effective hematopoiesis. Thus, alarmins and founder gene mutations in MDSs cause a common redox-sensitive inflammasome circuit. They are new candidates for

Not only apoptosis and pyroptosis are involved in increased cell death in MDS. Recently, possible further mechanism of cell death, necroptosis, in MDS has been described [72, 73]. Necroptosis is like pyroptosis associated with membrane permeabilization and the release of damage-associated molecular patterns (DAMPs) such as alarmins. Alarmins bind Toll-like receptor 4 (TLR4) and activate

The effects of lenalidomide in non-del(5q) are thought to be secondary to modulation of the immune system. Hyperactivated T cells inhibit hematopoiesis. Immunosuppressive therapies with antithymocyte globulin alone and in combination with prednisone or cyclosporine show response rates between 25 and 40% [75, 76]. The studies discussed in this and other chapters of this book will help to translate our knowledge of genetic aberrations and of pathophysiological mechanisms in MDS into clinical use in diagnosis, prognosis, and therapy. Novel agents developed on the basis of this knowledge (luspatercept, rigosertib, immune checkpoint inhibitors, venetoclax, and others) are in clinical trials and will help in relapsed/

The work of our group in this area was supported by the research project for conceptual development of research organization (00023736; Institute of Hematology and Blood Transfusion, Prague) from the Ministry of Health of the

the transcription factor NF-κB and inflammation [74].

**4**

## **Author details**

Ota Fuchs Institute of Hematology and Blood Transfusion, Prague, Czech Republic

\*Address all correspondence to: ota.fuchs@uhkt.cz

© 2019 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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[3] Shastri A, Will B, Steidl U, Verma A. Stem and progenitor cell alterations in myelodysplastic syndromes. Blood. 2017;**129**(12):1586-1594. DOI: 10.1182/ blood-2016-10-696062

[4] Nazha A, Sekeres MA. Precision medicine in myelodysplastic syndromes and leukemias: Lessons from sequential mutations. Annual Review of Medicine. 2017;**68**:127-137. DOI: 10.1146/ annurev-med-062915-095637

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[50] Kim HK, Ko TH, Nyamaa B, Lee SR, Kim N, Ko KS, et al. Cereblon in health and disease. Pflügers Archiv. 2016;**468**(8):1299-1309. DOI: 10.1007/ s00424-016-1854-1

[51] Jonasova A, Bokorova R, Polak J, Vostry M, Kostecka A, Hajkova H, et al. High level of full-length cereblon mRNA in lower risk myelodysplastic syndrome with isolated 5q deletion is implicated in the efficacy of lenalidomide. European Journal of Haematology. 2015;**95**(1): 27-34. DOI: 10.1111/ejh.12457

[52] Fischer ES, Böhm K, Lydeard JR, Yang H, Stadler MB, Cavadini S, et al. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature. 2014;**512**(7512): 49-53. DOI: 10.1038/nature13527

[53] Krönke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2014;**343**(6168):301-305. DOI: 10.1126/ science. 1244851

[54] Krönke J, Fink EC, Hollenbach PW, MacBeth KJ, Hurst SN, Udeshi ND, et al. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature. 2015;**523**(7559):183-188. DOI: 10.1038/nature14610

[55] Schneider RK, Ademà V, Heckl D, Järås M, Mallo M, Lord AM, et al. Role of casein kinase 1A1 in the biology and targeted therapy of del(5q) MDS. Cancer Cell. 2014;**26**(4):509-520. DOI: 10.1016/j.ccr. 2014.08.001

[56] Smith AE, Kulasekararaj AG, Jiang J, Mian S, Mohamedali A, Gaken J, et al. CSNK1A1 mutations and isolated del(5q) abnormality in myelodysplastic syndrome: A retrospective mutational analysis. The Lancet Haematology. 2015;**2**(5):e212-e221. DOI: 10.1016/ S2352-3026(15)00050-2

[57] Heuser M, Meggendorfer M, Cruz MM, Fabisch J, Klesse S, Köhler L, et al. Frequency and prognostic impact of casein kinase 1A1 mutations in MDS patients with deletion of chromosome 5q. Leukemia. 2015;**29**(9):1942-1945. DOI: 10.1038/leu.2015.49

[58] Negoro E, Radiovoyevitch T, Polprasert C, Adema V, Hosono N, Makishima H, et al. Molecular predictors of response in patients with myeloid neoplasms treated with lenalidomide. Leukemia. 2016;**30**(12):2405-2409. DOI: 10.1038/ leu.2016.228

[59] Martinez-Høyer S, Mo A, Deng D, Jiang J, Docking R, Li J, et al. Resistance to lenalidomide in del(5q) MDS is mediated by inhibition of drug-induced megakaryocytic differentiation. Blood. 2018;**132**:176. DOI: 10.1182/ blood-2018-176

[60] List A, Ebert BL, Fenaux P. A decade of progress in myelodysplastic syndrome with chromosome 5q deletion. Leukemia. 2018;**32**(7):1493- 1499. DOI: 10.1038/s41375-018-0029-9

[61] Belickova M, Vesela J, Jonasova A, Pejsova B, Votavova H, Merkerova MD, et al. TP53 mutation variant allele frequency is a potential predictor for clinical outcome of patients with lower-risk myelodysplastic syndromes. Oncotarget. 2016;**7**(24):36266-36279. DOI: 10.18632/oncotarget.9200

[62] Basiorka AA, McGraw KL, De Ceuninck L, Griner LN, Zhang L, Clark JA, et al. Lenalidomide stabilizes the erythropoietin receptor by inhibiting

the E3 ubiquitin ligase RNF41. Cancer Research. 2016;**76**(12):3531-3540. DOI: 10.1158/0008-5472.CAN-15-1756

[63] McGraw KL, Fuhler GM, Johnson JO, Clark JA, Caceres GC, Sokol L, et al. Erythropoietin receptor signaling is membrane raft dependent. PLoS One. 2012;**7**(4):e34477. DOI: 10.1371/journal. pone.0034477

[64] McGraw KL, Basiorka AA, Johnson JO, Clark J, Caceres G, Padron E, et al. Lenalidomide induces lipid raft assembly to enhance erythropoietin receptor signaling in myelodysplastic syndrome progenitors. PLoS One. 2014;**9**(12):e114249. DOI: 10.1371/ journal.pone.0114249

[65] Komrokji RS, Lancet JE, Swern AS, Chen N, Paleveda J, Lush R, et al. Combined treatment with lenalidomide and epoetin alfa in lower-risk patients with myelodysplastic syndrome. Blood. 2012;**120**(17):3419-3424. DOI: 10.1182/ blood-2012-03-415661

[66] Toma A, Kosmider O, Chevret S, Delaunay J, Stamatoullas A, Rose C, et al. Lenalidomide with or without erythropoietin in transfusiondependent erythropoiesis-stimulating agent-refractory lower-risk MDS without 5q deletion. Leukemia. 2016;**30**(4):897-905. DOI: 10.1038/ leu.2015.296

[67] Jonasova A, Neuwirtova R, Polackova H, Siskova M, Stopka T, Cmunt E, et al. Lenalidomide treatment in lower risk myelodysplastic syndromes—The experience of a Czech hematology center. (Positive effect of erythropoietin ± prednisone addition to lenalidomide in refractory or relapsed patients). Leukemia Research. 2018;**69**:12-17. DOI: 10.1016/j. leukres.2018.03.015

[68] Narla A, Dutt S, McAuley JR, Al-Shahrour F, Hurst S, McConkey M, et al. Dexamethasone and

**11**

*Introductory Chapter: Progress in Myelodysplastic Syndrome Area*

Immunosuppressive therapy: Exploring an underutilized treatment option for myelodysplastic syndrome. Clinical Lymphoma, Myeloma & Leukemia. 2016;**16**(Suppl):S44-S48. DOI: 10.1016/j.

[76] Stahl M, Zeidan AM. Lenalidomide use in myelodysplastic syndromes: Insights into the biologic mechanisms and clinical applications. Cancer. 2017;**123**(10):1703-1713. DOI: 10.1002/

clml.2016.02.017

cncr.30585

*DOI: http://dx.doi.org/10.5772/intechopen.84594*

lenalidomide have distinct functional effects on erythropoiesis. Blood. 2011;**118**(8):2296-2304. DOI: 10.1182/

[69] Komrokji RS, Al Ali NH, Padron E, Cogle C, Tinsley S, Sallman D, et al. Lenalidomide and prednisone in low and intermediate-1 IPSS risk, nondel(5q) MDS patients: A phase II clinical trial. Clinical Lymphoma, Myeloma & Leukemia. 2019. DOI: 10.1016/j.

[70] Basiorka AA, McGraw KL, Eksioglu EA, Chen X, Johnson J, Zhang L, et al. The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype. Blood.

2016;**128**(25):2960-2975. DOI: 10.1182/

[71] Sallman DA, Cluzeau T, Basiorka AA, List A. Unraveling the pathogenesis of MDS: The NLRP3 inflammasome and pyroptosis drive the MDS phenotype. Frontiers in Oncology. 2016;**6**:151. DOI:

[72] Croker BA, Kelliher MA. BIDding on necroptosis in MDS. Blood. 2019;**133**(2):103-104. DOI: 10.1182/

[73] Wagner PN, Shi Q , Salisbury-Ruf CT, Zou J, Savona MR, Fedoriw Y, et al. Increased Ripk1-mediated bone marrow necroptosis leads to myelodysplasia and bone marrow failure in mice. Blood. 2019;**133**(2):107-120. DOI: 10.1182/

blood-2010-11-318543

clml.2018.12.014

blood-2016-07-730556

10.3389/fonc.2016.00151

blood-2018-11-886242

blood-2018-05-847335

[74] Ping Z, Chen S, Hermans SJF, Kenswil KJG, Feyen J, van Dijk C, et al. Activation of NF-κB driven inflammatory programs in mesenchymal elements attenuates

hematopoiesis in low-risk

myelodysplastic syndromes. Leukemia. 2018. DOI: 10.1038/s41375-018-0267-x

[75] Haider M, Al Ali N, Padron E, Epling-Burnette P, Lancet J, List A, et al. *Introductory Chapter: Progress in Myelodysplastic Syndrome Area DOI: http://dx.doi.org/10.5772/intechopen.84594*

lenalidomide have distinct functional effects on erythropoiesis. Blood. 2011;**118**(8):2296-2304. DOI: 10.1182/ blood-2010-11-318543

*Recent Developments in Myelodysplastic Syndromes*

the E3 ubiquitin ligase RNF41. Cancer Research. 2016;**76**(12):3531-3540. DOI: 10.1158/0008-5472.CAN-15-1756

[63] McGraw KL, Fuhler GM, Johnson JO, Clark JA, Caceres GC, Sokol L, et al. Erythropoietin receptor signaling is membrane raft dependent. PLoS One. 2012;**7**(4):e34477. DOI: 10.1371/journal.

[64] McGraw KL, Basiorka AA, Johnson JO, Clark J, Caceres G, Padron E, et al. Lenalidomide induces lipid raft assembly to enhance erythropoietin receptor signaling in myelodysplastic syndrome progenitors. PLoS One. 2014;**9**(12):e114249. DOI: 10.1371/

[65] Komrokji RS, Lancet JE, Swern AS, Chen N, Paleveda J, Lush R, et al. Combined treatment with lenalidomide and epoetin alfa in lower-risk patients with myelodysplastic syndrome. Blood. 2012;**120**(17):3419-3424. DOI: 10.1182/

[66] Toma A, Kosmider O, Chevret S, Delaunay J, Stamatoullas A, Rose C, et al. Lenalidomide with or without erythropoietin in transfusion-

dependent erythropoiesis-stimulating agent-refractory lower-risk MDS without 5q deletion. Leukemia. 2016;**30**(4):897-905. DOI: 10.1038/

treatment in lower risk myelodysplastic syndromes—The experience of a Czech hematology center. (Positive effect of erythropoietin ± prednisone addition to lenalidomide in refractory or relapsed patients). Leukemia Research. 2018;**69**:12-17. DOI: 10.1016/j.

[67] Jonasova A, Neuwirtova R, Polackova H, Siskova M, Stopka T, Cmunt E, et al. Lenalidomide

[68] Narla A, Dutt S, McAuley JR, Al-Shahrour F, Hurst S, McConkey M, et al. Dexamethasone and

pone.0034477

journal.pone.0114249

blood-2012-03-415661

leu.2015.296

leukres.2018.03.015

[56] Smith AE, Kulasekararaj AG, Jiang J, Mian S, Mohamedali A, Gaken J, et al. CSNK1A1 mutations and isolated del(5q) abnormality in myelodysplastic syndrome: A retrospective mutational analysis. The Lancet Haematology. 2015;**2**(5):e212-e221. DOI: 10.1016/

[57] Heuser M, Meggendorfer M, Cruz MM, Fabisch J, Klesse S, Köhler L, et al. Frequency and prognostic impact of casein kinase 1A1 mutations in MDS patients with deletion of chromosome 5q. Leukemia. 2015;**29**(9):1942-1945.

S2352-3026(15)00050-2

DOI: 10.1038/leu.2015.49

leu.2016.228

blood-2018-176

[58] Negoro E, Radiovoyevitch T, Polprasert C, Adema V, Hosono N, Makishima H, et al. Molecular predictors of response in patients with myeloid neoplasms treated with lenalidomide. Leukemia.

2016;**30**(12):2405-2409. DOI: 10.1038/

[59] Martinez-Høyer S, Mo A, Deng D, Jiang J, Docking R, Li J, et al. Resistance to lenalidomide in del(5q) MDS is mediated by inhibition of drug-induced

megakaryocytic differentiation. Blood. 2018;**132**:176. DOI: 10.1182/

[60] List A, Ebert BL, Fenaux P. A decade of progress in myelodysplastic syndrome with chromosome 5q deletion. Leukemia. 2018;**32**(7):1493- 1499. DOI: 10.1038/s41375-018-0029-9

[61] Belickova M, Vesela J, Jonasova A, Pejsova B, Votavova H, Merkerova MD, et al. TP53 mutation variant allele frequency is a potential predictor for clinical outcome of patients with lower-risk myelodysplastic syndromes. Oncotarget. 2016;**7**(24):36266-36279. DOI: 10.18632/oncotarget.9200

[62] Basiorka AA, McGraw KL, De Ceuninck L, Griner LN, Zhang L, Clark JA, et al. Lenalidomide stabilizes the erythropoietin receptor by inhibiting

**10**

[69] Komrokji RS, Al Ali NH, Padron E, Cogle C, Tinsley S, Sallman D, et al. Lenalidomide and prednisone in low and intermediate-1 IPSS risk, nondel(5q) MDS patients: A phase II clinical trial. Clinical Lymphoma, Myeloma & Leukemia. 2019. DOI: 10.1016/j. clml.2018.12.014

[70] Basiorka AA, McGraw KL, Eksioglu EA, Chen X, Johnson J, Zhang L, et al. The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype. Blood. 2016;**128**(25):2960-2975. DOI: 10.1182/ blood-2016-07-730556

[71] Sallman DA, Cluzeau T, Basiorka AA, List A. Unraveling the pathogenesis of MDS: The NLRP3 inflammasome and pyroptosis drive the MDS phenotype. Frontiers in Oncology. 2016;**6**:151. DOI: 10.3389/fonc.2016.00151

[72] Croker BA, Kelliher MA. BIDding on necroptosis in MDS. Blood. 2019;**133**(2):103-104. DOI: 10.1182/ blood-2018-11-886242

[73] Wagner PN, Shi Q , Salisbury-Ruf CT, Zou J, Savona MR, Fedoriw Y, et al. Increased Ripk1-mediated bone marrow necroptosis leads to myelodysplasia and bone marrow failure in mice. Blood. 2019;**133**(2):107-120. DOI: 10.1182/ blood-2018-05-847335

[74] Ping Z, Chen S, Hermans SJF, Kenswil KJG, Feyen J, van Dijk C, et al. Activation of NF-κB driven inflammatory programs in mesenchymal elements attenuates hematopoiesis in low-risk myelodysplastic syndromes. Leukemia. 2018. DOI: 10.1038/s41375-018-0267-x

[75] Haider M, Al Ali N, Padron E, Epling-Burnette P, Lancet J, List A, et al. Immunosuppressive therapy: Exploring an underutilized treatment option for myelodysplastic syndrome. Clinical Lymphoma, Myeloma & Leukemia. 2016;**16**(Suppl):S44-S48. DOI: 10.1016/j. clml.2016.02.017

[76] Stahl M, Zeidan AM. Lenalidomide use in myelodysplastic syndromes: Insights into the biologic mechanisms and clinical applications. Cancer. 2017;**123**(10):1703-1713. DOI: 10.1002/ cncr.30585

**13**

**Chapter 2**

**Abstract**

**1. Introduction**

*and Safa Shukry*

Diagnosis and Classification of

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by morphological dysplastic changes in one or more of the major hematopoietic cell lines. MDS can present with varying degrees of single or multiple cytopenias including neutropenia, anemia and thrombocytopenia. Presentation of MDS can range from asymptomatic to life threatening. MDS diagnosis and classification present important challenges, particularly in the distinction from benign conditions. French-American-British (FAB) classification proposed a classification based on easily obtainable laboratory information and was recommended in early and as modified by guidelines of new classification of World Health Organization (WHO). The strategy of diagnostic laboratory in MDS depends on morphological changes and is based on existence of dysplastic changes in the peripheral blood and bone marrow including peripheral blood smear, bone marrow aspirate smear and bone marrow trephine biopsy. The correct morphological interpretation and the use of cytogenetics, immunophenotyping, immunohistochemistry and molecular

Myelodysplastic Syndrome

*Gamal Abdul Hamid, Abdul Wahab Al-Nehmi*

analysis will give valuable information on diagnosis and prognosis.

**Keywords:** myelodysplasia, cytopenia, diagnostic criteria, classification

Myelodysplastic syndromes (MDS) are clonal stem cell disorders with a relatively heterogeneous spectrum, characterized by morphological dysplasia in hematopoietic cells and by bone marrow failure and varying degrees of peripheral blood cytopenias. MDS have been recognized for more than 70 years and named

The risks of MDS include infection, anemia, bleeding and transformation to acute myeloblastic leukemia (AML) in approximately 30% of cases. MDS incidence increased from less than 5/100,000 for patients less than 60 years to 36.2 per 100,000 in patients more than 80 year old and more common among men.

In the last 20 years, different MDS classification and prognostic scoring systems have been proposed [1]. French-American-British (FAB) classification was recommended in early and as modified by the World Health Organization (WHO). The WHO classification system uses percentages of blasts in bone marrow, ring sideroblasts and dysplastic changes to differentiate MDS subtypes. The International Prognostic Scoring System (IPSS) is based on a multivariate to evaluate the prognosis. The updated and recent scoring system combine with WHO classification

refractory anemia, oligoblastic leukemia and smoldering acute leukemia.

## **Chapter 2**
