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ArtikelJAK2 Exon 12 Mutations in Polycythemia Vera and Idiopathic Erythrocytosis  
Oleh: Scott, Linda M. ; Tong, Wei ; Levine, Ross L. ; Scott, Mike A. ; Beer, Philip A. ; Stratton, Michael R. ; Futreal, P. Andrew ; Erber, Wendy N. ; McMullin, Mary Frances ; Harrison, Claire N. ; Warren, Alan J. ; Gilliland, D. Gary ; Lodish, Harvey F.
Jenis: Article from Journal - ilmiah internasional
Dalam koleksi: The New England Journal of Medicine (keterangan: ada di Proquest) vol. 356 no. 05 (Feb. 2007), page 459.
Ketersediaan
  • Perpustakaan FK
    • Nomor Panggil: N08.K.2007.01
    • Non-tandon: 1 (dapat dipinjam: 0)
    • Tandon: tidak ada
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Isi artikelBACKGROUND The V617F mutation, which causes the substitution of phenylalanine for valine at position 617 of the Janus kinase OAK) 2 gene UAK2), 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. BaB 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 ofleucine for lysine at position 539 ofJAK2. 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.
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