Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms

William Vainchenker and Robert Kralovics


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 MPL abnormally activate the cytokine receptor/JAK2 pathway and their downstream effectors, more particularly the STATs. The most frequent mutation, JAK2V617F, activates the three main myeloid cytokine receptors (EPOR, G-CSFR and MPL) whereas CALR or MPL mutants are restricted to MPL activation. This explains why JAK2V617F is associated with polycythemia vera (PV), 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 three 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 implicated in the development of anemia or pancytopenia. Both heterogeneity of classical MPNs and prognosis are determined by a specific genomic landscape i.e. 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 germline predisposition, inflammation and ageing. Delineation of these environmental factors will be important to better understand the precise pathogenesis of MPN.

  • Submitted October 17, 2016.
  • Accepted December 6, 2016.