title: Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.
abstract: BACKGROUND
  Human myeloproliferative disorders form a range of clonal haematological malignant diseases, the main members of which are polycythaemia vera, essential thrombocythaemia, and idiopathic myelofibrosis. The molecular pathogenesis of these disorders is unknown, but tyrosine kinases have been implicated in several related disorders. We investigated the role of the cytoplasmic tyrosine kinase JAK2 in patients with a myeloproliferative disorder.
  
  
  METHODS
  We obtained DNA samples from patients with polycythaemia vera, essential thrombocythaemia, or idiopathic myelofibrosis. The coding exons of JAK2 were bidirectionally sequenced from peripheral-blood granulocytes, T cells, or both. Allele-specific PCR, molecular cytogenetic studies, microsatellite PCR, Affymetrix single nucleotide polymorphism array analyses, and colony assays were undertaken on subgroups of patients.
  
  
  RESULTS
  A single point mutation (Val617Phe) was identified in JAK2 in 71 (97%) of 73 patients with polycythaemia vera, 29 (57%) of 51 with essential thrombocythaemia, and eight (50%) of 16 with idiopathic myelofibrosis. The mutation is acquired, is present in a variable proportion of granulocytes, alters a highly conserved valine present in the negative regulatory JH2 domain, and is predicted to dysregulate kinase activity. It was heterozygous in most patients, homozygous in a subset as a result of mitotic recombination, and arose in a multipotent progenitor capable of giving rise to erythroid and myeloid cells. The mutation was present in all erythropoietin-independent erythroid colonies.
  
  
  CONCLUSIONS
  A single acquired mutation of JAK2 was noted in more than half of patients with a myeloproliferative disorder. Its presence in all erythropoietin-independent erythroid colonies demonstrates a link with growth factor hypersensitivity, a key biological feature of these disorders.
  
  
  CONCLUSIONS
  Identification of the Val617Phe JAK2 mutation lays the foundation for new approaches to the diagnosis, classification, and treatment of myeloproliferative disorders.
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: E Joanna
authors.initials: EJ
authors.lastname: Baxter
authors.forename: Linda M
authors.initials: LM
authors.lastname: Scott
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.forename: Clare
authors.initials: C
authors.lastname: East
authors.forename: Nasios
authors.initials: N
authors.lastname: Fourouclas
authors.forename: Soheila
authors.initials: S
authors.lastname: Swanton
authors.forename: George S
authors.initials: GS
authors.lastname: Vassiliou
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Bench
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Boyd
authors.forename: Natasha
authors.initials: N
authors.lastname: Curtin
authors.forename: Mike A
authors.initials: MA
authors.lastname: Scott
authors.forename: Wendy N
authors.initials: WN
authors.lastname: Erber
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Green
mesh_terms: D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D003114:Colony-Forming Units Assay; D006098:Granulocytes / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053614:Janus Kinase 2; D019656:Loss of Heterozygosity; D009196:Myeloproliferative Disorders / Q000235:genetics*; D017354:Point Mutation; D011087:Polycythemia Vera / Q000235:genetics; D016133:Polymerase Chain Reaction; D055728:Primary Myelofibrosis / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013920:Thrombocythemia, Essential / Q000235:genetics
chemical_list: D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2