Author/Authors :
Walters، نويسنده , , Denise K. and Mercher، نويسنده , , Thomas and Gu، نويسنده , , Ting-Lei and OʹHare، نويسنده , , Thomas and Tyner، نويسنده , , Jeffrey W. and Loriaux، نويسنده , , Marc and Goss، نويسنده , , Valerie L. and Lee، نويسنده , , Kimberly A. and Eide، نويسنده , , Christopher A. and Wong، نويسنده , , Matthew J. and Stoffregen، نويسنده , , Eric P. and McGreevey، نويسنده , , Laura and Nardone، نويسنده , , Julie and Moore، نويسنده , , Sandra A. and Crispino، نويسنده , , John and Boggon، نويسنده , , Titus J. and Heinrich، نويسنده , , Michael C. and Deininger، نويسنده , , Michael W. and Polakiewicz، نويسنده , , Roberto D. and Gilliland، نويسنده , , D. Gary and Druker، نويسنده , , Brian J.، نويسنده ,
Abstract :
Summary
ne 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. JAK3A572V, JAK3V722I, and JAK3P132T each transform Ba/F3 cells to factor-independent growth, and JAK3A572V 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.
