Activating alleles of JAK3 in acute megakaryoblastic leukemia

Denise K. Walters; 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

doi:10.1016/j.ccr.2006.06.002

Activating alleles of JAK3 in acute megakaryoblastic leukemia

Denise K. Walters, 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 GillilandBrian J. Druker

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Résumé

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.

langue originale	Anglais
Pages (de - à)	65-75
Nombre de pages	11
journal	Cancer Cell
Volume	10
Numéro de publication	1
Les DOIs	https://doi.org/10.1016/j.ccr.2006.06.002
état	Publié - 1 janv. 2006
Modification externe	Oui

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10.1016/j.ccr.2006.06.002

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Walters, D. K., Mercher, T., Gu, T. L., O'Hare, T., Tyner, J. W., Loriaux, M., Goss, V. L., Lee, K. A., Eide, C. A., Wong, M. J., Stoffregen, E. P., McGreevey, L., Nardone, J., Moore, S. A., Crispino, J., Boggon, T. J., Heinrich, M. C., Deininger, M. W., Polakiewicz, R. D., ... Druker, B. J. (2006). Activating alleles of JAK3 in acute megakaryoblastic leukemia. Cancer Cell, 10(1), 65-75. https://doi.org/10.1016/j.ccr.2006.06.002

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title = "Activating alleles of JAK3 in acute megakaryoblastic leukemia",

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. 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.",

keywords = "CELLCYCLE",

author = "Walters, {Denise K.} and Thomas Mercher and Gu, {Ting Lei} and Thomas O'Hare and Tyner, {Jeffrey W.} and Marc Loriaux and Goss, {Valerie L.} and Lee, {Kimberly A.} and Eide, {Christopher A.} and Wong, {Matthew J.} and Stoffregen, {Eric P.} and Laura McGreevey and Julie Nardone and Moore, {Sandra A.} and John Crispino and Boggon, {Titus J.} and Heinrich, {Michael C.} and Deininger, {Michael W.} and Polakiewicz, {Roberto D.} and Gilliland, {D. Gary} and Druker, {Brian J.}",

note = "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. ",

year = "2006",

month = jan,

day = "1",

doi = "10.1016/j.ccr.2006.06.002",

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Walters, DK, Mercher, T, Gu, TL, O'Hare, T, Tyner, JW, Loriaux, M, Goss, VL, Lee, KA, Eide, CA, Wong, MJ, Stoffregen, EP, McGreevey, L, Nardone, J, Moore, SA, Crispino, J, Boggon, TJ, Heinrich, MC, Deininger, MW, Polakiewicz, RD, Gilliland, DG & Druker, BJ 2006, 'Activating alleles of JAK3 in acute megakaryoblastic leukemia', Cancer Cell, VOL. 10, Numéro 1, p. 65-75. https://doi.org/10.1016/j.ccr.2006.06.002

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.

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DO - 10.1016/j.ccr.2006.06.002

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JF - Cancer Cell

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