Abstract:

Chronic myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoiesis resulting from the transformation of a hematopoietic stem cell, with abnormal proliferation of one or more of the myeloid lineages. The Philadelphia-negative (Ph-negative) classical MPNs mainly comprise polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The identification of JAK2V617F mutation in early 2005 followed by the discovery of JAK2 exon 12 and MPL gene mutations, have modified the understanding of the pathogenesis of these various disease entities. However, all these mutations fail to explain the heterogeneity of these entities. This has led to the discovery of a series of mutations in patients with MPN involving the negative regulators of signaling pathways, such as LNK, mutated or deleted transcription factors such as IKZF1 and Tp53, a member of the MAPK signaling pathway NRAS, and mutations in epigenetic regulators such as TET2, ASXL1, EZH2 and IDH1/2. Mutations in CALR were discovered in a majority of JAK2V617F- and MPL-negative ET and PMF patients. Among MPN patients, genetic abnormalities affecting epigenetic regulation are often expressed in those harboring JAK2, MPL or CALR mutations which imply a collaboration between these two classes of mutations in MPN pathogenesis. Despite the recent insights into the molecular events of these diseases, it has become increasingly clear that these mutations were not MPN specific. There are likely yet additional unidentified genetic events which contribute to MPN development. We review recent data on the impact of genetic and epigenetic abnormalities in MPN pathogenesis. Key Words: Essential thrombocythemia, myeloproliferative disorders, polycythemia vera, primary myelofibrosis,

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