title: A gain-of-function mutation of JAK2 in myeloproliferative disorders.
abstract: BACKGROUND
  Polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are clonal myeloproliferative disorders arising from a multipotent progenitor. The loss of heterozygosity (LOH) on the short arm of chromosome 9 (9pLOH) in myeloproliferative disorders suggests that 9p harbors a mutation that contributes to the cause of clonal expansion of hematopoietic cells in these diseases.
  
  
  METHODS
  We performed microsatellite mapping of the 9pLOH region and DNA sequencing in 244 patients with myeloproliferative disorders (128 with polycythemia vera, 93 with essential thrombocythemia, and 23 with idiopathic myelofibrosis).
  
  
  RESULTS
  Microsatellite mapping identified a 9pLOH region that included the Janus kinase 2 (JAK2) gene. In patients with 9pLOH, JAK2 had a homozygous G-->T transversion, causing phenylalanine to be substituted for valine at position 617 of JAK2 (V617F). All 51 patients with 9pLOH had the V617F mutation. Of 193 patients without 9pLOH, 66 were heterozygous for V617F and 127 did not have the mutation. The frequency of V617F was 65 percent among patients with polycythemia vera (83 of 128), 57 percent among patients with idiopathic myelofibrosis (13 of 23), and 23 percent among patients with essential thrombocythemia (21 of 93). V617F is a somatic mutation present in hematopoietic cells. Mitotic recombination probably causes both 9pLOH and the transition from heterozygosity to homozygosity for V617F. Genetic evidence and in vitro functional studies indicate that V617F gives hematopoietic precursors proliferative and survival advantages. Patients with the V617F mutation had a significantly longer duration of disease and a higher rate of complications (fibrosis, hemorrhage, and thrombosis) and treatment with cytoreductive therapy than patients with wild-type JAK2.
  
  
  CONCLUSIONS
  A high proportion of patients with myeloproliferative disorders carry a dominant gain-of-function mutation of JAK2.
authors.affiliation: Department of Research, Experimental Hematology, University Hospital Basel, Basel, Switzerland.
authors.forename: Robert
authors.initials: R
authors.lastname: Kralovics
authors.forename: Francesco
authors.initials: F
authors.lastname: Passamonti
authors.forename: Andreas S
authors.initials: AS
authors.lastname: Buser
authors.forename: Soon-Siong
authors.initials: SS
authors.lastname: Teo
authors.forename: Ralph
authors.initials: R
authors.lastname: Tiedt
authors.forename: Jakob R
authors.initials: JR
authors.lastname: Passweg
authors.forename: Andre
authors.initials: A
authors.lastname: Tichelli
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.forename: Radek C
authors.initials: RC
authors.lastname: Skoda
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D016022:Case-Control Studies; D002899:Chromosomes, Human, Pair 9; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D053614:Janus Kinase 2; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008969:Molecular Sequence Data; D017354:Point Mutation; D011087:Polycythemia Vera / Q000235:genetics*; D055728:Primary Myelofibrosis / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D013922:Thrombocytosis / Q000235:genetics*
chemical_list: D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2