Activating alleles of JAK3 in acute megakaryoblastic leukemia

Denise K. Walters, Thomas Mercher, Ting Lei Gu, Thomas O'Hare, Jeffrey 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 Heinrich, Michael W. Deininger, Roberto D. Polakiewicz, D. Gary Gilliland & 1 others Brian Druker

Research output: Contribution to journalArticle

239 Citations (Scopus)

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 2006

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Leukemia, Megakaryoblastic, Acute
Alleles
Acute Myeloid Leukemia
Protein-Tyrosine Kinases
Mutation
Proteomics
Tyrosine
Mass Spectrometry
Intercellular Signaling Peptides and Proteins
Leukemia
Cell Line
Neoplasms
Proteins

Keywords

  • CELLCYCLE

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Activating alleles of JAK3 in acute megakaryoblastic leukemia. / Walters, Denise K.; Mercher, Thomas; Gu, Ting Lei; O'Hare, Thomas; Tyner, Jeffrey; 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; Deininger, Michael W.; Polakiewicz, Roberto D.; Gilliland, D. Gary; Druker, Brian.

In: Cancer Cell, Vol. 10, No. 1, 07.2006, p. 65-75.

Research output: Contribution to journalArticle

Walters, DK, Mercher, T, Gu, TL, O'Hare, T, Tyner, J, Loriaux, M, Goss, VL, Lee, KA, Eide, CA, Wong, MJ, Stoffregen, EP, McGreevey, L, Nardone, J, Moore, SA, Crispino, J, Boggon, TJ, Heinrich, M, Deininger, MW, Polakiewicz, RD, Gilliland, DG & Druker, B 2006, 'Activating alleles of JAK3 in acute megakaryoblastic leukemia', Cancer Cell, vol. 10, no. 1, pp. 65-75. https://doi.org/10.1016/j.ccr.2006.06.002
Walters, Denise K. ; Mercher, Thomas ; Gu, Ting Lei ; O'Hare, Thomas ; Tyner, Jeffrey ; 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 ; Deininger, Michael W. ; Polakiewicz, Roberto D. ; Gilliland, D. Gary ; Druker, Brian. / Activating alleles of JAK3 in acute megakaryoblastic leukemia. In: Cancer Cell. 2006 ; Vol. 10, No. 1. pp. 65-75.
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