Pathogenesis and Mutations of Myeloproliferative Neoplasms: An Overview

Abstract

Chronic myeloproliferative neoplasms (MPNs), clonal disorders of hematopoietic system resulting in abnormal proliferation of one or more hematopoietic cell lineages, express different clinical, hematologic and biological features. The majority of classical MPNs -95% of polycythemia vera (PV) and half of essential thrombocythemia (ET) and myelofibrosis (MF) patients- display alterations in the JAK2 gene.  JAK2 wild-type ET, and MF patients lack features of PV. Driver mutations in pathogenesis of Philadelpiha-negative MPNs - JAK2, MPL and calreticulin (CALR)- all play pivotal roles in cytokine signaling in hematopoiesis. Negative regulators of signaling pathways, LNK and CBL are infrequently targeted genes in MPNs. Mutated or deleted transcription factors such as IKZF1, EZH2, Tp53 and RUNX1, are present in a low proportion of patients with MPN. Some of these factors, such as IKZF1 and Tp53, were associated with transformation to acute myeloid leukemia (AML), yet their prognostic impact needs to be elucidated. Mutations of CHEK2, the tumor suppressor gene against uncontrolled cell growth, were associated with susceptibility to ET. Mutations of NRAS gene, a member of  MAPK signaling pathway frequently mutated in MPNs, seem to affect expression of JAK2 target genes and  are primarily associated with transformation to AML. Mutations in epigenetic regulators including TET2, DNMT3A, ASXL1, EZH2, and IDH1/2 were described in MPNs and other myeloid malignancies at variable frequencies. The somatic mutation of SRSF2, one of the RNA splicing machinery genes, was associated with worse survival and increased leukemic transformation in PMF. Alterations in DNMT3A, ASXL1, EZH2, and IDH1/2 are more frequent in PMF than PV and ET. Recent studies suggest that for Ph-negative MPNs, mutations affecting epigenetic regulation might be prognostically more relevant than mutations affecting JAK-STAT signaling. Mutations in CALR were newly discovered in a majority of JAK2V617F- and MPL-negative ET and MF patients. In MPNs, genetic abnormalities affecting epigenetic regulation are often expressed in patients carrying JAK2, MPL, or CALR mutations, indicating a cooperation between these two classes of mutations in MPN pathogenesis. This review summarizes pathogenesis and molecular events of MPNs.