Blood Journal
Leading the way in experimental and clinical research in hematology

New mutations and pathogenesis of myeloproliferative neoplasms

  1. William Vainchenker13,
  2. François Delhommeau1,2,4,
  3. Stefan N. Constantinescu5,6, and
  4. Olivier A. Bernard2,3,7
  1. 1Inserm, UMR1009, Institut Gustave Roussy, Villejuif, France;
  2. 2Institut Gustave Roussy, Villejuif, France;
  3. 3Université Paris-Sud, Villejuif, France;
  4. 4Université Pierre et Marie Curie, Hôpital Saint Antoine, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France;
  5. 5Ludwig Institute for Cancer Research, Brussels, Belgium;
  6. 6Université Catholique de Louvain, de Duve Institute, Brussels, Belgium; and
  7. 7Inserm, UMR 985, Villejuif, France


Myeloproliferative neoplasms (MPNs) are clonal disorders characterized by excessive production of mature blood cells. In the majority of classic MPN—polycythemia vera, essential thrombocythemia, and primitive myelofibrosis—driver oncogenic mutations affecting Janus kinase 2 (JAK2) or MPL lead to constitutive activation of cytokine-regulated intracellular signaling pathways. LNK, c-CBL, or SOCSs (all negative regulators of signaling pathways), although 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 greater frequency than in de novo acute myeloid leukemias. Loss-of-function mutations in 3 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 subclone during the chronic phase and, together with cooperating mutations, promote blast crisis. Their precise roles in hematopoiesis and in the pathogenesis of MPN, as well as their prognostic impact and potential as a therapeutic target, are currently under investigation.

  • Submitted February 10, 2011.
  • Accepted May 6, 2011.
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