JAK2 V617F in myeloid disorders: what do we know now, and where are we headed?
Activating tyrosine kinase (TK) mutations disrupt cellular proliferation and survival pathways and are increasingly recognized as a fundamental cause of human cancers. Until very recently, the only TK mutations widely observed in myeloid neoplasia were the BCR/ABL1 fusions characteristic of chronic myeloid leukemia and some acute leukemias, and FLT3 activating mutations in a minority of acute myeloid leukemias. Several rare TK mutations are found in various atypical myeloproliferative disorders, but big pieces of the pathobiological puzzle were glaringly missing. In the first half of 2005, one gap was filled in: 7 studies identified the same acquired amino acid substitution (V617F) in the Janus kinase 2 (JAK2) TK in large numbers of patients with diverse clonal myeloid disorders. Most affected patients suffer from the classic BCR/ABL1-negative myeloproliferative disorders (MPD), especially polycythemia vera (74% of n = 506), but a subset of people with essential thrombocythemia (36% of n = 339) or myelofibrosis with myeloid metaplasia (44% of n = 127) bear the identical mutation, as do a few individuals with myelodysplastic syndromes or an atypical myeloid disorder (7% of n = 556). This long-sought common mutation in BCR/ABL1-negative MPD raises many provocative biological and clinical questions, and demands re-evaluation of prevailing diagnostic algorithms for erythrocytosis and thrombocytosis. JAK2 V617F may provide novel molecular targets for drug therapy, and suggests other places to seek cooperating mutations or mutations associated with similar phenotypes. The story of this exciting finding will unfold rapidly in the years ahead, and ongoing developments will be important for all hematologists to understand.
Nelson
Maria E
ME
Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Steensma
David P
DP
D000818:Animals; D006801:Humans; D053614:Janus Kinase 2; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2