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

Research output: Contribution to journalArticle

245 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)65-75
Number of pages11
JournalCancer Cell
Volume10
Issue number1
DOIs
StatePublished - Jul 1 2006

Keywords

  • CELLCYCLE

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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  • Cite this

    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