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Blood, 1 November 2004, Vol. 104, No. 9, pp. 2867-2872. Prepublished online as a Blood First Edition Paper on July 15, 2004; DOI 10.1182/blood-2003-12-4446. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-12-4446v1 104/9/2867    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 Clark, J. J. Articles by Gilliland, D. G. Search for Related Content PubMed PubMed Citation Articles by Clark, J. J. Articles by Gilliland, D. G. Related Collections Neoplasia Oncogenes and Tumor Suppressors Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Variable sensitivity of FLT3 activation loop mutations to the small molecule tyrosine kinase inhibitor MLN518 Jennifer J. Clark, Jan Cools, David P. Curley, Jin-Chen Yu, Nathalie A. Lokker, Neill A. Giese, and D. Gary Gilliland From the Division of Hematology/Oncology, Brigham and Women's Hospital, Boston; Howard Hughes Medical Institute, Harvard Medical School, Boston; Dana Farber Cancer Institute, Boston; Boston Children's Hospital, MA; and Millennium Pharmaceuticals, South San Francisco, CA. FLT3 is constitutively activated by internal tandem duplications (ITDs) in the juxtamembrane domain or by activation loop mutations in acute myeloid leukemia (AML). We tested the sensitivity of 8 activation loop mutations to the small molecule FLT3 inhibitor, MLN518. Each FLT3 activation loop mutant, including D835Y, D835A, D835E, D835H, D835N, D835V, D835del, and I836del, transformed Ba/F3 cells to factor-independent proliferation and had constitutive tyrosine kinase activation, as assessed by FLT3 autophosphorylation and activation of downstream effectors, including STAT5 and ERK. MLN518 inhibited FLT3 autophosphorylation and phosphorylation of STAT5 and ERK in FLT3-ITD-transformed Ba/F3 cells with an IC50 (50% inhibition of cell viability) of approximately 500 nM. However, there was a broad spectrum of sensitivity among the 8 activation loop mutants, with IC50 ranging from approximately 500 nM to more than 10 µM for the inhibition of phosphorylation of FLT3, STAT5, and ERK. The relative sensitivity of the mutants to MLN518 in biochemical assays correlated with the cellular IC50 for cytokine-independent proliferation of FLT3-transformed Ba/F3 cells in the presence of MLN518. Thus, certain activation loop mutations in FLT3 simultaneously confer resistance to small molecule inhibitors. These findings have implications for the evaluation of responses in clinical trials with FLT3 inhibitors and provide a strategy to screen for compounds that can overcome resistance. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. M. Loriaux, R. L. Levine, J. W. Tyner, S. Frohling, C. Scholl, E. P. Stoffregen, G. Wernig, H. Erickson, C. A. Eide, R. Berger, et al. High-throughput sequence analysis of the tyrosine kinome in acute myeloid leukemia Blood, May 1, 2008; 111(9): 4788 - 4796. [Abstract] [Full Text] [PDF] E. V. Barry, J. J. Clark, J. Cools, J. Roesel, and D. G. Gilliland Uniform sensitivity of FLT3 activation loop mutants to the tyrosine kinase inhibitor midostaurin Blood, December 15, 2007; 110(13): 4476 - 4479. [Abstract] [Full Text] [PDF] O. Piloto, M. Wright, P. Brown, K.-T. 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