Epigenetics and mutations in chronic myeloproliferative neoplasms.

The BCR-ABL1-negative classic myeloproliferative neoplasms, polycythemia vera (PV), essential thrombocytemia (ET) and primary myelofibrosis are clonal stem cell disorders associated with an increased production of mature blood cells belonging preferentially to one cell linage. They share substantial phenotypic mimicry, can undergo phenotypic shifts (from PV to ET and vice versa) as well as evolution to myelofibrosis (postPV/post-ET myelofibrosis), and all eventually progress to leukemia. The hypothesis that hypersensitivity of hematopoietic stem and progenitor cells to cytokines might largely account for the pathogenesis of myeloproliferative neoplasms has been corroborated by the discovery of mutations that affect cytoplasmic proteins involved in cytokine signaling, either resulting in a gain-of-function (JAK2 and MPL) or a loss-of-function (CBL and LNK). Dysregulation of tyrosine kinases is a recurrent theme in chronic myeloid neoplasms, as exemplified by the constitutive activation of ABL caused by oligomerization of the BCR-ABL fusion protein in chronic myelogenous leukemia, the gain-of-function mutation of the tyrosine kinase receptor c-KIT in mastocytosis, and the activation of platelet-derived growth factor receptor-α or -b and fibroblast growth factor receptor in hypereosinophilic disorders. However, high-throughput genomic analyses of myeloproliferative neoplasms have recently identified a second group of mutations that affect proteins involved in the epigenetic regulation of transcription, such as TET2, ASXL1 and EZH2. These abnormalities can occur in association and/or with mutations targeting tyrosine kinases.