Activating alleles of JAK3 in acute megakaryoblastic leukemia

被引：254

作者：

Walters, Denise K.

Mercher, Thomas

Gu, Ting-Lei

O'Hare, Thomas

Tyner, Jeffrey W.

Loriaux, Marc

Goss, Valerie L.

Lee, Kimberly A.

Eide, Christopher A.

Wong, Matthew J.

Stoffregen, Eric P.

McGreevey, Laura

Nardone, Julie

Moore, Sandra A.

Crispino, John

Boggon, Titus J.

Heinrich, Michael C.

Deininger, Michael W.

Polakiewicz, Roberto D.

Gilliland, D. Gary

Druker, Brian J. ^{[1
]}

机构：

[1] Howard Hughes Med Inst, Portland, OR 97239 USA

[2] Oregon Hlth & Sci Univ, Dept Hematol & Med Oncol, Portland, OR 97239 USA

[3] Harvard Univ, Sch Med, Howard Hughes Med Inst, Brigham & Womens Hosp, Boston, MA 02115 USA

[4] Cell Signaling Technol Inc, Danvers, MA 01923 USA

[5] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97239 USA

[6] Portland VA Med Ctr, Portland, OR 97239 USA

[7] Univ Chicago, Ben May Inst Canc Res, Chicago, IL 60637 USA

[8] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA

来源：

CANCER CELL | 2006年 / 10卷 / 01期

关键词：

D O I：

10.1016/j.ccr.2006.06.002

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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(P132T), and JAK3P132T 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.

引用

页码：65 / 75

页数：11

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