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Prepublished online as a Blood First Edition Paper on March 27, 2003; DOI 10.1182/blood-2002-11-3441. This Article Full Text (PDF) All Versions of this Article: 2002-11-3441v1 102/2/646    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 Grundler, R. Articles by Duyster, J. Search for Related Content PubMed PubMed Citation Articles by Grundler, R. Articles by Duyster, J. Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Submitted November 14, 2002 Accepted March 18, 2003 Sensitivity towards tyrosine kinase inhibitors varies between different activating mutations of the FLT3 receptor Rebekka Grundler, Christian Thiede, Cornelius Miething, Christine Steudel, Christian Peschel, and Justus Duyster* Department of Internal Medicine III, Laboratory of Leukemogenesis, Technical University of Munich, Munich, Germany Med. Klinik und Poliklinik I, Universitaetsklinikum Carl Gustav Carus der Technischen Universitaet Dresden, Dresden, Germany * Corresponding author; email: justus.duyster{at}lrz.tum.de. Activating mutations of FLT3 have been detected in patients with acute myeloid leukemia (AML). Two distinct types of FLT3 mutations are most common: Internal tandem duplication (ITD) of sequences coding for the juxtamembrane domain and point mutations at codon 835 (D835) within the kinase domain. Both types of mutations constitutively activate the tyrosine kinase activity of FLT3 in experimental systems and result in factor independent proliferation of Ba/F3 and 32D cells. Very recently, novel mutations within the activation loop were identified in AML patients: Deletion of isoleucine 836 (I836del) and an exchange of isoleucine 836 to methionine plus an arginine insertion (I836M+R). In order to examine whether the I836 mutations result in constitutive activation of the FLT3 receptor, we introduced both mutant FLT3 cDNAs transiently into HEK 293 cells. Both mutant FLT3 receptors were constitutively autophosphorylated in the absence of ligand and kinase activity led to constitutive activation of downstream signaling cascades as determined by activation of the STAT5 pathway. When stably expressed in the growth factor dependent cell lines Ba/F3 and 32D both deletion and insertion mutants led to factor independent proliferation, indicating that both mutants have transforming capabilities. We then examined the sensitivity of the FLT3 ITD, FLT3 D835Y and the novel FLT3 receptor mutants towards the kinase inhibitors AG1296, PKC412 and SU5614. We show that these FLT3 kinase inhibitors have distinct inhibitory potencies against different activating FLT3 receptor mutants. These results suggest that it may be useful to determine the exact kind of FLT3 mutation when applying receptor kinase inhibitors in clinical trials. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Use of FLT3 inhibitors in leukemia: a wrench in the activation loop D. Gary Gilliland Blood 2003 102: 418. [Full Text] [PDF] This article has been cited by other articles: N. von Bubnoff, R. A. Engh, E. Aberg, J. Sanger, C. 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