JAK2 V617F and beyond: role of genetics and aberrant signaling in the pathogenesis of myeloproliferative neoplasms

Expert Rev Hematol. 2010 Jun;3(3):323-37. doi: 10.1586/ehm.10.28.


Dysregulated signaling is a hallmark of chronic myeloproliferative neoplasms (MPNs), as evidenced by the identification of the activating JAK2 V617F somatic mutation in almost all patients with polycythemia vera (PV) and 50-60% of essential thrombocythemia and primary myelofibrosis patients. These disorders are clinically distinct, raising the question of how a single mutation can result in such phenotypic diversity. Mouse models have demonstrated that the level of JAK2 V617F expression can modulate the phenotype, and clinical studies of JAK2 V617F allele burden have reported similar findings. It has also been hypothesized that one or more pre-JAK2 V617F events may modify the MPN phenotype. However, the molecular basis of JAK2 V617F-negative essential thrombocythemia and primary myelofibrosis remains largely unexplained. Mutations in the TET2 gene have been identified in both JAK2 V617F-positive and -negative MPNs and other myeloid neoplasms, but their functional and clinical significance have yet to be clarified. In addition, recent reports have identified a specific germline haplotype that increases the predisposition to MPNs. The role of inhibitory pathways (e.g., SOCS and LNK) in regulating JAK-STAT signaling in MPNs is being increasingly recognized. The implications of these findings and their clinical relevance are the focus of this article.

Publication types

  • Review

MeSH terms

  • Alleles
  • Animals
  • Female
  • Genetic Association Studies
  • Humans
  • Janus Kinase 2* / antagonists & inhibitors
  • Janus Kinase 2* / genetics
  • Mice
  • Mutation*
  • Phenotype
  • Polycythemia Vera* / enzymology
  • Polycythemia Vera* / genetics
  • Polycythemia Vera* / therapy
  • Primary Myelofibrosis* / enzymology
  • Primary Myelofibrosis* / genetics
  • Primary Myelofibrosis* / therapy
  • Protein Kinase Inhibitors / administration & dosage*
  • STAT Transcription Factors / metabolism*
  • Signal Transduction / genetics*
  • Thrombocythemia, Essential* / enzymology
  • Thrombocythemia, Essential* / genetics
  • Thrombocythemia, Essential* / therapy


  • Protein Kinase Inhibitors
  • STAT Transcription Factors
  • Janus Kinase 2