TY - JOUR
T1 - Activating alleles of JAK3 in acute megakaryoblastic leukemia
AU - Walters, Denise K.
AU - Mercher, Thomas
AU - Gu, Ting Lei
AU - O'Hare, Thomas
AU - Tyner, Jeffrey W.
AU - Loriaux, Marc
AU - Goss, Valerie L.
AU - Lee, Kimberly A.
AU - Eide, Christopher A.
AU - Wong, Matthew J.
AU - Stoffregen, Eric P.
AU - McGreevey, Laura
AU - Nardone, Julie
AU - Moore, Sandra A.
AU - Crispino, John
AU - Boggon, Titus J.
AU - Heinrich, Michael C.
AU - Deininger, Michael W.
AU - Polakiewicz, Roberto D.
AU - Gilliland, D. Gary
AU - Druker, Brian J.
N1 - Funding Information:
This study was supported by Howard Hughes Medical Institute (D.G.G. and B.J.D.), a grant from the Doris Duke Charitable Foundation (D.G.G. and B.J.D.), the Leukemia and Lymphoma Society (D.G.G. and B.J.D.), the NIH (D.G.G.), and a Veterans Affairs Merit Review Grant (M.C.H.). Funding was also provided by Cell Signaling for the authors at Cell Signaling. T.M. is a recipient of a Special Fellow Award from the Leukemia and Lymphoma Society. J.W.T. is supported by an OHSU NIH Cancer Biology Training Grant. T.J.B. is supported by an American Society of Hematology Basic Research Scholar Award. T.-L.G., V.L.G., K.A.L., J.N., and R.D.P. are employees of Cell Signaling Technology.
PY - 2006/1/1
Y1 - 2006/1/1
N2 - 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. 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.
AB - 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. 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.
KW - CELLCYCLE
UR - http://www.scopus.com/inward/record.url?scp=33745713168&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2006.06.002
DO - 10.1016/j.ccr.2006.06.002
M3 - Article
C2 - 16843266
AN - SCOPUS:33745713168
SN - 1535-6108
VL - 10
SP - 65
EP - 75
JO - Cancer Cell
JF - Cancer Cell
IS - 1
ER -