| Literature DB >> 16843266 |
Denise K Walters1, Thomas Mercher, Ting-Lei Gu, Thomas O'Hare, Jeffrey W Tyner, Marc Loriaux, Valerie L Goss, Kimberly A Lee, Christopher A Eide, Matthew J Wong, Eric P Stoffregen, Laura McGreevey, Julie Nardone, Sandra A Moore, John Crispino, Titus J Boggon, Michael C Heinrich, Michael W Deininger, Roberto D Polakiewicz, D Gary Gilliland, Brian J Druker.
Abstract
Tyrosine kinases are aberrantly activated in numerous malignancies, including acute myeloid leukemia (AML). To identify tyrosine kinases activated in AML, we developed a screening strategy that rapidly identifies tyrosine-phosphorylated proteins using mass spectrometry. This allowed the identification of an activating mutation (A572V) in the JAK3 pseudokinase domain in the acute megakaryoblastic leukemia (AMKL) cell line CMK. Subsequent analysis identified two additional JAK3 alleles, V722I and P132T, in AMKL patients. JAK3(A572V), JAK3(V722I), and JAK3(P132T) each transform Ba/F3 cells to factor-independent growth, and JAK3(A572V) confers features of megakaryoblastic leukemia in a murine model. These findings illustrate the biological importance of gain-of-function JAK3 mutations in leukemogenesis and demonstrate the utility of proteomic approaches to identifying clinically relevant mutations.Entities:
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Year: 2006 PMID： 16843266 DOI： 10.1016/j.ccr.2006.06.002
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743