**3.5 Meyloproliferative neoplasm (MPN)**

Myeloproliferative neoplasms (MPN) can be denifed by a group of diseases characterised by increased proliferation of erythroid, megakaryocytic, or granulocytic.

According to WHO (2008) MPN regroups clonal disorders of myeloid progenitor cells., MPN have been classified into 3 groups. Also called Philadelphia chromosome-negative (Ph −), myeloproliferative neoplasms (MPNs), include polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (both primary (PMF) and secondary (post-ET/PV MF)) [39].

The 3 MPN entities are characterised by their clinical heterogeinicity, establishment of precise diagnosis at disease onset can be a real challeng for physician. The World Health Organisation (WHO) established revision for diagnostic and defined new criteria for MPN on 2016, (**Figure 2**) [40].

The first gene mutation described in 2005, JAK2-V617F, turned out to be the most important and most frequently recurring somatic mutation in MPN [6–9]. The frequency ofJAK2-V617F is around 95% in PV and between 50% and 60% in ET and PMF [41].

MPN patients who do not present mutations in any of the aforementioned genes (so-named "triple-negative" MPN cases), but those patients seem to have hyperactive JAK2 signalling [42].

The *JAK2*V617F mutation arises in a multipotent haematopoietic progenitor, is present in all myeloid lineages.

The *JAK2*V617F is mainly restricted to classical MPNs with the exception of refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T). It can rarely be found in some other malignant hemopathies [43, 44].

Concerning MPL mutation, it have been demonstrated that two types of mutation exist: (*MPL*; the thrombopoietin [TPO] receptor [TPOR]) mutations located in exon 10, both have been reported on association with MPNs.

**97**

*Haematological Malignancies: Overview of the Recent Progresses in Genetics*

The most frequent are mutations on the tryptophan W515 located at the boundary of the transmembrane and the cytosolic domains of MPL, the most prominent

At the end of 2013, frameshift mutations in the *CALR* gene were identified in the

There are great differences in the frequency between type 1 and type 2 muta-

*CALR* mutations reported are often heterozygous, only few cases of homozygous mutations have been reported, more particularly for type 2 mutations [43].

*It has been also proved that CALR* mutants gives a stronger clonal advantage when

In 2010, somatic mutations in exon 2 of *LNK* (*SH2B3*), an adaptor protein which

The 3 MPN oncogenes are considered as true drivers of the disease phenotype with JAK2 exon 12 giving only an erythrocytosis phenotype, JAK2V617F giving rise to ET, PV, and MF, whereas CALR mutant and MPLW515L/K/A are associated with

The 3 main driver mutations do not explain the entire heterogeneity of the

 MPNs. Like other hematologic malignancies, the mutations in epigenetic regulators can be observed, such as MDS and AML; and some of the gene mutations, such as TET2

Some studies suggest that the presence of mutations in TET2, EZH2, and ASXL1

Selective JAK2 inhibitors, (SAR302503 and BMS911543), combination JAK2/JAK3 inhibitor (CEP701), and combination JAK2/TYK2 inhibitor (pacritinib) have shown

Major progress has been achieved in understanding the molecular pathogenesis

While the clinical utility of this genetic and epigenetic revolution, novel therapeutic agents aimed at the aberrant underlying processes are more and more included rational combination therapies. This knowledge increase outcome for haematological diseases patients, and are helpful to develop therapies based on

of haematological malignancies in a very short period of 10 years.

insights into the genetic basis of these haematological neoplasms.

Few time after the discovery of the JAK2 V617F mutation, multiple small molecule inhibitors were developed for therapeutic use: ruxolitinib, is the first JAK1 and JAK2 inhibitor, approved in August 2011 for use in intermediate and high-risk PMF

ET and PMF (50%–60% ET and 75% PMF).

MPNs. The 3 main driver mutations do not explain the entire

Mutations on *MPL*W515 are restricted to ET (around 3%) and PMF

regulates JAK2 activation, were detected in 2 patients (PMF and ET).

ET and MF, resembling the phenotype observed in patients.

and ASXL1, are more frequent in MDS than in MPN.

are associated with hight risk of secondary AML.

*DOI: http://dx.doi.org/10.5772/intechopen.96913*

mutations being MPLW515L and K [42].

heterogeneity of the classical *BCR-ABL*<sup>−</sup>

and post PV/ET myelofibrosis.

clinical efficacy in phase I/II trials.

**4. Conclusion**

and *MPL*<sup>−</sup>

(around 5%).

majority of *JAK2*<sup>−</sup>

tions in ET and PMF.

classical *BCR-ABL*<sup>−</sup>

compared with *JAK2*V617F.

#### **Figure 2.**

*2016 WHO classification of myeloid malignancies.*

*Haematological Malignancies: Overview of the Recent Progresses in Genetics DOI: http://dx.doi.org/10.5772/intechopen.96913*

The most frequent are mutations on the tryptophan W515 located at the boundary of the transmembrane and the cytosolic domains of MPL, the most prominent mutations being MPLW515L and K [42].

Mutations on *MPL*W515 are restricted to ET (around 3%) and PMF (around 5%).

At the end of 2013, frameshift mutations in the *CALR* gene were identified in the majority of *JAK2*<sup>−</sup> and *MPL*<sup>−</sup> ET and PMF (50%–60% ET and 75% PMF).

There are great differences in the frequency between type 1 and type 2 mutations in ET and PMF.

*CALR* mutations reported are often heterozygous, only few cases of homozygous mutations have been reported, more particularly for type 2 mutations [43].

*It has been also proved that CALR* mutants gives a stronger clonal advantage when compared with *JAK2*V617F.

In 2010, somatic mutations in exon 2 of *LNK* (*SH2B3*), an adaptor protein which regulates JAK2 activation, were detected in 2 patients (PMF and ET).

The 3 MPN oncogenes are considered as true drivers of the disease phenotype with JAK2 exon 12 giving only an erythrocytosis phenotype, JAK2V617F giving rise to ET, PV, and MF, whereas CALR mutant and MPLW515L/K/A are associated with ET and MF, resembling the phenotype observed in patients.

The 3 main driver mutations do not explain the entire heterogeneity of the classical *BCR-ABL*<sup>−</sup> MPNs. The 3 main driver mutations do not explain the entire heterogeneity of the classical *BCR-ABL*<sup>−</sup> MPNs.

Like other hematologic malignancies, the mutations in epigenetic regulators can be observed, such as MDS and AML; and some of the gene mutations, such as TET2 and ASXL1, are more frequent in MDS than in MPN.

Some studies suggest that the presence of mutations in TET2, EZH2, and ASXL1 are associated with hight risk of secondary AML.

Few time after the discovery of the JAK2 V617F mutation, multiple small molecule inhibitors were developed for therapeutic use: ruxolitinib, is the first JAK1 and JAK2 inhibitor, approved in August 2011 for use in intermediate and high-risk PMF and post PV/ET myelofibrosis.

Selective JAK2 inhibitors, (SAR302503 and BMS911543), combination JAK2/JAK3 inhibitor (CEP701), and combination JAK2/TYK2 inhibitor (pacritinib) have shown clinical efficacy in phase I/II trials.

## **4. Conclusion**

*Cytogenetics - Classical and Molecular Strategies for Analysing Heredity Material*

Myeloproliferative neoplasms (MPN) can be denifed by a group of diseases

According to WHO (2008) MPN regroups clonal disorders of myeloid progenitor cells., MPN have been classified into 3 groups. Also called Philadelphia chromosome-negative (Ph −), myeloproliferative neoplasms (MPNs), include polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (both

The 3 MPN entities are characterised by their clinical heterogeinicity, establishment of precise diagnosis at disease onset can be a real challeng for physician. The World Health Organisation (WHO) established revision for diagnostic and defined

The first gene mutation described in 2005, JAK2-V617F, turned out to be the most important and most frequently recurring somatic mutation in MPN [6–9]. The frequency ofJAK2-V617F is around 95% in PV and between 50% and 60% in ET and

MPN patients who do not present mutations in any of the aforementioned genes (so-named "triple-negative" MPN cases), but those patients seem to have hyperac-

The *JAK2*V617F mutation arises in a multipotent haematopoietic progenitor, is

Concerning MPL mutation, it have been demonstrated that two types of mutation exist: (*MPL*; the thrombopoietin [TPO] receptor [TPOR]) mutations located in

The *JAK2*V617F is mainly restricted to classical MPNs with the exception of refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T). It can

rarely be found in some other malignant hemopathies [43, 44].

exon 10, both have been reported on association with MPNs.

characterised by increased proliferation of erythroid, megakaryocytic, or

**3.5 Meyloproliferative neoplasm (MPN)**

primary (PMF) and secondary (post-ET/PV MF)) [39].

new criteria for MPN on 2016, (**Figure 2**) [40].

granulocytic.

PMF [41].

tive JAK2 signalling [42].

present in all myeloid lineages.

**96**

**Figure 2.**

*2016 WHO classification of myeloid malignancies.*

Major progress has been achieved in understanding the molecular pathogenesis of haematological malignancies in a very short period of 10 years.

While the clinical utility of this genetic and epigenetic revolution, novel therapeutic agents aimed at the aberrant underlying processes are more and more included rational combination therapies. This knowledge increase outcome for haematological diseases patients, and are helpful to develop therapies based on insights into the genetic basis of these haematological neoplasms.
