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Previous Volume 356:459-468 February 1, 2007 Number 5 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Supplementary Material Perspective by Tefferi, A. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear Related Article PubMed Citation

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.

Source Information

From the University of Cambridge (L.M.S., P.A.B., A.J.W., A.R.G.) and Addenbrooke's National Health Service Trust (M.A.S., W.N.E., A.J.W., A.R.G.) — both in Cambridge, United Kingdom; Whitehead Institute for Biomedical Research (W.T., H.F.L.) and Massachusetts Institute of Technology (H.F.L.) — both in Cambridge, MA; Brigham and Women's Hospital and Dana–Farber Cancer Institute, Harvard Medical School (R.L.L., D.G.G.), and Howard Hughes Medical Institute, Harvard Medical School (D.G.G.) — all in Boston; Wellcome Trust Sanger Institute, Hinxton, United Kingdom (M.R.S., P.A.F.); Queen's University, Belfast, Northern Ireland (M.F.M.); and St. Thomas' Hospital, London (C.N.H.).

Drs. Tong and Levine contributed equally to this article.

Address reprint requests to Dr. Anthony R. Green at the Department of Haematology, Cambridge Institute for Medical Research, Hills Rd., Cambridge CB2 2XY, United Kingdom, or at arg1000{at}cam.ac.uk.

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