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Blood, 1 December 2005, Vol. 106, No. 12, pp. 3958-3961. Prepublished online as a Blood First Edition Paper on August 4, 2005; DOI 10.1182/blood-2005-02-0583. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-02-0583v1 106/12/3958    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Cammenga, J. Articles by Stocking, C. Search for Related Content PubMed PubMed Citation Articles by Cammenga, J. Articles by Stocking, C. Related Collections Neoplasia Apoptosis Oncogenes and Tumor Suppressors Signal Transduction Brief Reports Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Brief report Extracellular KIT receptor mutants, commonly found in core binding factor AML, are constitutively active and respond to imatinib mesylate Jörg Cammenga, Stefan Horn, Ulla Bergholz, Gunhild Sommer, Peter Besmer, Walter Fiedler, and Carol Stocking From the Molecular Pathology Group at the Heinrich-Pette-Institut and the Department of Medicine II, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany; and the Developmental Biology Program, Sloan-Kettering Institute, New York, NY. Multiple genetic alterations are required to induce acute myelogenous leukemia (AML). Mutations in the extracellular domain of the KIT receptor are almost exclusively found in patients with AML carrying translocations or inversions affecting members of the core binding factor (CBF) gene family and correlate with a high risk of relapse. We demonstrate that these complex insertion and deletion mutations lead to constitutive activation of the KIT receptor, which induces factor-independent growth of interleukin-3 (IL-3)–dependent cells. Mutation of the evolutionary conserved amino acid D419 within the extracellular domain was sufficient to constitutively activate the KIT receptor, although high expression levels were required. Dose-dependent growth inhibition and apoptosis were observed using either the protein tyrosine kinase inhibitor imatinib mesylate (STI571, Gleevec) or by blocking the phosphoinositide-3-kinase (PI3K)–AKT pathway. Our data show that the addition of kinase inhibitors to conventional chemotherapy might be a new therapeutic option for CBF-AML expressing mutant KIT. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. G. Roberts, A. F. Odell, E. M. Byrnes, R. M. Baleato, R. Griffith, A. B. Lyons, and L. K. Ashman Resistance to c-KIT kinase inhibitors conferred by V654A mutation Mol. Cancer Ther., March 1, 2007; 6(3): 1159 - 1166. [Abstract] [Full Text] [PDF] J. Pan, A. Quintas-Cardama, H. M. Kantarjian, C. Akin, T. Manshouri, P. Lamb, J. E. Cortes, A. Tefferi, F. J. Giles, and S. Verstovsek EXEL-0862, a novel tyrosine kinase inhibitor, induces apoptosis in vitro and ex vivo in human mast cells expressing the KIT D816V mutation Blood, January 1, 2007; 109(1): 315 - 322. [Abstract] [Full Text] [PDF] P. Paschka, G. Marcucci, A. S. Ruppert, K. Mrozek, H. Chen, R. A. Kittles, T. Vukosavljevic, D. Perrotti, J. W. Vardiman, A. J. Carroll, et al. Adverse Prognostic Significance of KIT Mutations in Adult Acute Myeloid Leukemia With inv(16) and t(8;21): A Cancer and Leukemia Group B Study J. Clin. Oncol., August 20, 2006; 24(24): 3904 - 3911. [Abstract] [Full Text] [PDF]

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