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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 (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 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 Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 5, 2004 Accepted May 31, 2004 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 G Gilliland Division of Hematology/Oncology, Brigham and Women's Hospital, Boston, MA, USA; Pediatric Hematology/Oncology, Dana Farber Cancer Institute,Harvard Medical School, Boston, MA, USA; Adult Hematology and Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA Division of Hematology/Oncology, Brigham and Women's Hospital, Boston, MA, USA Pediatric Hematology and Oncology, Boston Children's Hospital, Boston, MA, USA Division of Hematology/Oncology, Brigham and Women's Hospital, Boston, MA, USA; Division of Hematology/Oncology, Howard Hughes Medical Institute, Boston, MA, USA; Pediatric Hematology/Oncology, Dana Farber Cancer Institute,Harvard Medical School, Boston, MA, USA * Corresponding author; email: Jennifer_Clark{at}dfci.harvard.edu. FLT3 is constitutively activated by internal tandem duplications (ITDs) in the juxtamembrane domain or by activation loop mutations in 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 of ~500 nM. However, there was a broad spectrum of sensitivity among the 8 activation loop mutants with IC50's ranging from ~500 nM to >10mM for 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 evaluation of response 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: A. Nordigarden, M. Kraft, P. Eliasson, V. Labi, E. W.-F. Lam, A. Villunger, and J.-I. Jonsson BH3-only protein Bim more critical than Puma in tyrosine kinase inhibitor-induced apoptosis of human leukemic cells and transduced hematopoietic progenitors carrying oncogenic FLT3 Blood, March 5, 2009; 113(10): 2302 - 2311. [Abstract] [Full Text] [PDF] M. Kurokawa, C. Zhao, T. 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