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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 3, 2005 Accepted July 27, 2005 Extracellular KIT receptor mutants, commonly found in core binding factor AML, are constitutively active and respond to imatinib mesylate Jorg Cammenga, Stefan Horn, Ulla Bergholz, Gunhild Sommer, Peter Besmer, Walter Fiedler, and Carol Stocking* Molecular Pathology Group, Heinrich-Pette-Institut, Hamburg, Germany Molecular Pathology Group, Heinrich-Pette-Institut, Hamburg, Germany; Developmental Biology Program, Sloan-Kettering Institute, New York, New York, USA Developmental Biology Program, Sloan-Kettering Institute, New York, New York, USA Department of Medicine II, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany * Corresponding author; email: stocking{at}hpi.uni-hamburg.de. 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 AML patients 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 IL3-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 or by blocking the 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: O. Fuster, E. Barragan, P. Bolufer, J. Cervera, M. J. Larrayoz, A. Jimenez-Velasco, J. Martinez-Lopez, A. Valencia, F. Moscardo, and M. A. Sanz Rapid Detection of KIT Mutations in Core-Binding Factor Acute Myeloid Leukemia Using High-Resolution Melting Analysis J. Mol. Diagn., September 1, 2009; 11(5): 458 - 463. [Abstract] [Full Text] [PDF] T. Haferlach Molecular Genetic Pathways as Therapeutic Targets in Acute Myeloid Leukemia Hematology, January 1, 2008; 2008(1): 400 - 411. [Abstract] [Full Text] [PDF] 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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