Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms

Abstract

The genetic landscape of classical myeloproliferative neoplasm (MPN) is in large part elucidated. The MPN-restricted driver mutations, including those in JAK2, calreticulin (CALR), and myeloproliferative leukemia virus (MPL), abnormally activate the cytokine receptor/JAK2 pathway and their downstream effectors, more particularly the STATs. The most frequent mutation, JAK2V617F, activates the 3 main myeloid cytokine receptors (erythropoietin receptor, granulocyte colony-stimulating factor receptor, and MPL) whereas CALR or MPL mutants are restricted to MPL activation. This explains why JAK2V617F is associated with polycythemia vera, essential thrombocythemia (ET), and primary myelofibrosis (PMF) whereas CALR and MPL mutants are found in ET and PMF. Other mutations in genes involved in epigenetic regulation, splicing, and signaling cooperate with the 3 MPN drivers and play a key role in the PMF pathogenesis. Mutations in epigenetic regulators TET2 and DNMT3A are involved in disease initiation and may precede the acquisition of JAK2V617F. Other mutations in epigenetic regulators such as EZH2 and ASXL1 also play a role in disease initiation and disease progression. Mutations in the splicing machinery are predominantly found in PMF and are implicated in the development of anemia or pancytopenia. Both heterogeneity of classical MPNs and prognosis are determined by a specific genomic landscape, that is, type of MPN driver mutations, association with other mutations, and their order of acquisition. However, factors other than somatic mutations play an important role in disease initiation as well as disease progression such as germ line predisposition, inflammation, and aging. Delineation of these environmental factors will be important to better understand the precise pathogenesis of MPN.

Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms

“…12,43,52 A number of observations are consistent with the notion that JAK2 (V617F)-mutant ET and PV represent a continuum in which it may be difficult to define boundaries. 53,54 Although JAK2 (V617F)-homozygous subclones are found both in ET and PV patients, the expansion of a dominant homozygous subclone occurs almost exclusively in PV patients.…”

“…*Canonical MPL exon 10 mutations include W515L/K/A/R, S505N/C, and V501A (transmembrane domain of MPL); noncanonical MPL mutations (outside exon 10) include T119I, S204F/P, E230G, Y252H (extracellular domain) and Y591D/N (intracellular domain). 12 BLOOD, 9 FEBRUARY 2017 x VOLUME 129, NUMBER 6 CLASSICAL MYELOPROLIFERATIVE NEOPLASMS 681…”

“…Indeed, triple-negative PMF is similar to the myelodysplastic syndrome associated with bone marrow fibrosis, a condition characterized by hypercellular bone marrow, multilineage dysplasia, severe cytopenia involving high transfusion requirement, unfavorable cytogenetics, and poor survival. 32 Bone marrow fibrosis can be driven by somatic mutation of myeloid tumor-suppressor genes like EZH2 33 or SRSF2, 12 and therefore this abnormality is not infrequent in myeloid neoplasms other than PMF. Patients with triple-negative PMF should be investigated using a gene panel sequencing approach, 34 and exclusion of the BCR-ABL1 rearrangement is important in these cases.…”

Screening for MPN Mutations in Cases of Deep Vein Thrombosis and/or Pulmonary Embolism: What We have learnt from Studies

“…The allele burden was quantified in 21 cases, with a median value of 3.4% (0.75-32). This level is low and more commonly associated with ET than with other MPNs [1]. Two patients were previously followed for MPNs at the time of their thrombosis and eight patients were secondary diagnosed as MPN (6 ET, 3 PV and 1 unspecified MPN) during the first year of followup.…”

“…JAK2V617F is a somatic acquired mutation, located in its pseudo-kinase domain which transforms JAK2 in a gain-of-function enzyme, by continuous activation of the kinase domain despite the low level of circulating EPO. It induces an independent growth from cytokines (i.e., EPO for immature red cells) and a hypersensibility to these cytokines (if they are added to cells cultures) [1]. The result is an increase of mature cells in bone marrow and blood, inducing hyperviscosity and thromboses which are the main complications (20 to 50% of the patients).…”