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Blood, 15 December 2007, Vol. 110, No. 13, pp. 4476-4479. Prepublished online as a Blood First Edition Paper on September 7, 2007; DOI 10.1182/blood-2007-07-101238. This Article Full Text Full Text (PDF) Supplemental Table All Versions of this Article: blood-2007-07-101238v1 110/13/4476    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Barry, E. V. Articles by Gilliland, D. G. Search for Related Content PubMed PubMed Citation Articles by Barry, E. V. Articles by Gilliland, D. G. Related Collections Oncogenes and Tumor Suppressors Signal Transduction Brief Reports Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Brief Report Uniform sensitivity of FLT3 activation loop mutants to the tyrosine kinase inhibitor midostaurin Elly V. Barry1,2, Jennifer J. Clark1,2, Jan Cools3, Johannes Roesel4, and D. Gary Gilliland1,5 1 Dana-Farber Cancer Institute, 2 Children's Hospital Boston, Harvard Medical School, Boston, MA; 3 Department of Molecular and Developmental Genetics, Flanders Institute for Biotechnology (VIB), Katholieke Universiteit (KU) Leuven, Leuven, Belgium; 4 Novartis Pharma, Basel, Switzerland; and 5 Brigham and Women's Hospital, and the Howard Hughes Medical Institute, Harvard Medical School, Boston, MA Small molecule inhibitors that target fms-like tyrosine kinase 3 (FLT3)–activating mutations have potential in the treatment of leukemias. However, certain mutations can simultaneously activate the tyrosine kinase, and confer resistance to small molecule inhibitors. We therefore tested the sensitivity of 8 FLT3 activation loop mutants to midostaurin. Each mutant conferred IL-3 factor–independent proliferation to Ba/F3 cells, and each resulted in the constitutive activation of FLT3 and its targets, signal transducer and activator of transcription 5 (STAT5) and extracellular stimuli-responsive kinase (ERK). For each mutant tested, midostaurin inhibited cell growth and phosphorylation of FLT3, STAT5, and ERK. In contrast, midostaruin did not inhibit Ba/F3 cells stably transduced with FLT3-internal tandem duplications containing a G697R mutation that confers resistance to midostaurin, demonstrating that midostaurin inhibition of FLT3 activation loop mutants was not due to off-target effects. We conclude that midostaurin is a potent inhibitor of a spectrum of FLT3 activation loop mutations, and that acute myeloid leukemia patients with such mutations are potential candidates for clinical trials involving midostaurin. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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