title: JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis.
abstract: BACKGROUND
  The V617F mutation, which causes the substitution of phenylalanine for valine at position 617 of the Janus kinase (JAK) 2 gene (JAK2), is often present in patients with polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis. However, the molecular basis of these myeloproliferative disorders in patients without the V617F mutation is unclear.
  
  
  METHODS
  We searched for new mutations in members of the JAK and signal transducer and activator of transcription (STAT) gene families in patients with V617F-negative polycythemia vera or idiopathic erythrocytosis. The mutations were characterized biochemically and in a murine model of bone marrow transplantation.
  
  
  RESULTS
  We identified four somatic gain-of-function mutations affecting JAK2 exon 12 in 10 V617F-negative patients. Those with a JAK2 exon 12 mutation presented with an isolated erythrocytosis and distinctive bone marrow morphology, and several also had reduced serum erythropoietin levels. Erythroid colonies could be grown from their blood samples in the absence of exogenous erythropoietin. All such erythroid colonies were heterozygous for the mutation, whereas colonies homozygous for the mutation occur in most patients with V617F-positive polycythemia vera. BaF3 cells expressing the murine erythropoietin receptor and also carrying exon 12 mutations could proliferate without added interleukin-3. They also exhibited increased phosphorylation of JAK2 and extracellular regulated kinase 1 and 2, as compared with cells transduced by wild-type JAK2 or V617F JAK2. Three of the exon 12 mutations included a substitution of leucine for lysine at position 539 of JAK2. This mutation resulted in a myeloproliferative phenotype, including erythrocytosis, in a murine model of retroviral bone marrow transplantation.
  
  
  CONCLUSIONS
  JAK2 exon 12 mutations define a distinctive myeloproliferative syndrome that affects patients who currently receive a diagnosis of polycythemia vera or idiopathic erythrocytosis.
authors.affiliation: University of Cambridge, Cambridge, United Kingdom.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Scott
authors.forename: Wei
authors.initials: W
authors.lastname: Tong
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: Mike A
authors.initials: MA
authors.lastname: Scott
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beer
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
authors.forename: Wendy N
authors.initials: WN
authors.lastname: Erber
authors.forename: Mary Frances
authors.initials: MF
authors.lastname: McMullin
authors.forename: Claire N
authors.initials: CN
authors.lastname: Harrison
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Warren
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: Harvey F
authors.initials: HF
authors.lastname: Lodish
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Green
mesh_terms: D000818:Animals; D001483:Base Sequence; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D005091:Exons; D006579:Heterozygote; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism; D011086:Polycythemia / Q000235:genetics*; D011087:Polycythemia Vera / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D010770:Phosphotransferases; C507924:JAK2 protein, human; D053614:Janus Kinase 2