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Blood, 15 April 2005, Vol. 105, No. 8, pp. 3319-3321. Prepublished online as a Blood First Edition Paper on December 23, 2004; DOI 10.1182/blood-2004-06-2068. This Article Full Text (PDF) All Versions of this Article: 2004-06-2068v1 105/8/3319    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 Kohl, T. M Articles by Spiekermann, K. Search for Related Content PubMed PubMed Citation Articles by Kohl, T. M Articles by Spiekermann, K. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 9, 2004 Accepted December 14, 2004 KIT exon 8 mutations associated with core binding factor (CBF) - acute myeloid leukemia (AML) cause hyperactivation of the receptor in response to stem cell factor Tobias M Kohl, Susanne Schnittger, Joachim W Ellwart, Wolfgang Hiddemann, and Karsten Spiekermann* Department of Medicine III, University Hospital Grosshadern, Ludwig-Maximilians University, Clinical Cooperative Group 'Leukemia', Munich, Germany; GSF-National Research Center for Environment and Health, Munich, Germany; Institute of Molecular Immunology, Munich, Germany Department of Medicine III, University Hospital Grosshadern, Ludwig-Maximilians University, Clinical Cooperative Group 'Leukemia', Munich, Germany GSF-National Research Center for Environment and Health, Munich, Germany; Institute of Molecular Immunology, Munich, Germany * Corresponding author; email: k.spiekermann{at}gmx.de. KIT exon 8 mutations are located in the extracellular portion of the receptor and strongly associated with core binding factor (CBF) - acute myeloid leukemia (AML). To characterize the functional role of these mutants, we analyzed the pro-proliferative and antiapoptotic potential of three KIT exon 8 mutations in IL-3 dependent Ba/F3 cells. All KIT exon 8 mutants induced receptor hyperactivation in response to stem cell factor (SCF) stimulation in terms of proliferation and resistance towards apoptotic cell death. A representative KIT exon 8 mutant showed spontaneous receptor dimerization, phosphorylation of mitogen-activated protein kinase (MAPK) and conferred IL-3 independent growth to Ba/F3 cells. MAPK and PI3 kinase activation was essential for the phenotype of this mutant. Additionally, Imatinib inhibited proliferation of KIT exon 8 mutant expressing Ba/F3 cells. Our data show that KIT exon 8 mutations represent gain-of-function mutations and might represent a new molecular target for treatment of CBF leukemias. 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] S. Vempati, C. Reindl, U. Wolf, R. Kern, K. Petropoulos, V. M. Naidu, C. Buske, W. Hiddemann, T. M. Kohl, and K. Spiekermann Transformation by Oncogenic Mutants and Ligand-Dependent Activation of FLT3 Wild-type Requires the Tyrosine Residues 589 and 591 Clin. Cancer Res., July 15, 2008; 14(14): 4437 - 4445. [Abstract] [Full Text] [PDF] M. M. Loriaux, R. L. Levine, J. 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