1 New mutations and pathogenesis of myeloproliferative neoplasms

Myeloproliferative neoplasms (MPN) are clonal disorders characterized by excessive production of mature cells. In the majority of classic MPN- polycythemia vera, essential thrombocythemia and primitive myelofibrosis-driver oncogenic mutations affecting JAK2 or MPL lead to constitutive activation of cytokine-regulated intracellular signaling pathways. LNK, c-CBL or SOCSs (all negative regulators of signaling pathways), though infrequently targeted, may either drive the disease or synergize with JAK2 and MPL mutations. IZF1 deletions or TP53 mutations are mainly found at transformation phases and are present at higher frequency than in de novo AMLs. Loss-of-function mutations in three genes involved in epigenetic regulation, TET2, ASXL1 and EZH2, may be early events preceding JAK2V617F, but may also occur late during disease progression. They are more frequently observed in PMF than PV and ET and are also present in other types of malignant myeloid diseases. A likely hypothesis is that they facilitate clonal selection; allowing the dominance of the JAK2V617F subclon