A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera

Nature. 2005 Apr 28;434(7037):1144-8. doi: 10.1038/nature03546.


Myeloproliferative disorders are clonal haematopoietic stem cell malignancies characterized by independency or hypersensitivity of haematopoietic progenitors to numerous cytokines. The molecular basis of most myeloproliferative disorders is unknown. On the basis of the model of chronic myeloid leukaemia, it is expected that a constitutive tyrosine kinase activity could be at the origin of these diseases. Polycythaemia vera is an acquired myeloproliferative disorder, characterized by the presence of polycythaemia diversely associated with thrombocytosis, leukocytosis and splenomegaly. Polycythaemia vera progenitors are hypersensitive to erythropoietin and other cytokines. Here, we describe a clonal and recurrent mutation in the JH2 pseudo-kinase domain of the Janus kinase 2 (JAK2) gene in most (> 80%) polycythaemia vera patients. The mutation, a valine-to-phenylalanine substitution at amino acid position 617, leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model. As this mutation is also found in other myeloproliferative disorders, this unique mutation will permit a new molecular classification of these disorders and novel therapeutical approaches.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Bone Marrow Transplantation
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Erythropoietin / pharmacology
  • Exons / genetics
  • Humans
  • Interleukin-3 / pharmacology
  • Janus Kinase 2
  • Mice
  • Mutation / genetics*
  • Polycythemia
  • Polycythemia Vera / genetics
  • Polycythemia Vera / metabolism*
  • Polycythemia Vera / pathology*
  • Protein-Tyrosine Kinases / genetics*
  • Protein-Tyrosine Kinases / metabolism*
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction* / drug effects


  • Interleukin-3
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Erythropoietin
  • Protein-Tyrosine Kinases
  • JAK2 protein, human
  • Jak2 protein, mouse
  • Janus Kinase 2