Activating alleles of JAK3 in acute megakaryoblastic leukemia

• Published in: Cancer cell 2006-07, Vol.10 (1), p.65-75
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Alleles; Animals; Apoptosis - drug effects; Benzamides; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; CELLCYCLE; Humans; Imatinib Mesylate; Janus Kinase 2; Janus Kinase 3; K562 Cells; Leukemia, Experimental - genetics; Leukemia, Experimental - metabolism; Leukemia, Experimental - pathology; Leukemia, Megakaryoblastic, Acute - genetics; Leukemia, Megakaryoblastic, Acute - metabolism; Leukemia, Megakaryoblastic, Acute - pathology; Mice; Mice, Inbred C57BL; Models, Molecular; Mutant Proteins - chemistry; Mutant Proteins - genetics; Mutant Proteins - metabolism; Phosphorylation - drug effects; Piperazines - pharmacology; Protein Kinase Inhibitors - pharmacology; Protein Structure, Tertiary - genetics; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Pyrimidines - pharmacology; RNA, Small Interfering - genetics; TYK2 Kinase
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2006.06.002

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.