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Blood, 15 September 2004, Vol. 104, No. 6, pp. 1855-1858. Prepublished online as a Blood First Edition Paper on June 3, 2004; DOI 10.1182/blood-2004-02-0712. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-02-0712v1 104/6/1855    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 Jiang, J. Articles by Sellers, W. R. Search for Related Content PubMed PubMed Citation Articles by Jiang, J. Articles by Sellers, W. R. Related Collections Neoplasia Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Brief report Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML Jingrui Jiang, J. Guillermo Paez, Jeffrey C. Lee, Ronghai Bo, Richard M. Stone, Daniel J. DeAngelo, Ilene Galinsky, Brian M. Wolpin, Anna Jonasova, Paula Herman, Edward A. Fox, Titus J. Boggon, Michael J. Eck, Ellen Weisberg, James D. Griffin, D. Gary Gilliland, Matthew Meyerson, and William R. Sellers From the Departments of Medical Oncology, Pediatric Oncology, and Cancer Biology, Dana-Farber Cancer Institute, Boston; the Department of Medicine, Division of Hematology and Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston; the Departments of Medicine, Pediatrics, Pathology, and Biological Chemistry and Molecular Pharmacology Harvard Medical School, Boston; and the Broad Institute at the Massachusetts Institute of Technology and Harvard, Cambridge, MA. The FLT3 receptor is activated by juxtamembrane insertion mutations and by activation loop point mutations in patients with acute myeloid leukemia (AML). In a systematic tyrosine kinase gene exon resequencing study, 21 of 24 FLT3 exons were sequenced in samples from 53 patients with AML, 9 patients with acute lymphoblastic leukemia (ALL), and 3 patients with myelodysplasia samples. Three patients had novel point mutations at residue N841 that resulted in a change to isoleucine in 2 samples and to tyrosine in 1 sample. Introduction of FLT3-N841I cDNA into Ba/F3 cells led to interleukin-3 (IL-3)–independent proliferation, receptor phosphorylation, and constitutive activation of signal transducer and activator of transcription 5 (STAT5) and extracellular regulatory kinase (ERK), suggesting that the N841I mutation confers constitutive activity to the receptor. An FLT3 inhibitor (PKC412) inhibited the growth of Ba/F3-FLT3N841I cells (IC50 10 nM), but not of wild-type Ba/F3 cells cultured with IL-3. PKC412 also reduced tyrosine phosphorylation of the mutant receptor and inhibited STAT5 phosphorylation. Examination of the FLT3 autoinhibited structure showed that N841 is the key residue in a hydrogen-bonding network that likely stabilizes the activation loop. These results suggest that mutations at N841 represent a significant new activating mutation in patients with AML and that patients with such mutations may respond to small-molecule FLT3 inhibitors such as PKC412. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: N. von Bubnoff, R. A. Engh, E. Aberg, J. Sanger, C. Peschel, and J. Duyster FMS-Like Tyrosine Kinase 3-Internal Tandem Duplication Tyrosine Kinase Inhibitors Display a Nonoverlapping Profile of Resistance Mutations In vitro Cancer Res., April 1, 2009; 69(7): 3032 - 3041. [Abstract] [Full Text] [PDF] E. Weisberg, J. Roesel, G. Bold, P. Furet, J. Jiang, J. Cools, R. D. Wright, E. Nelson, R. Barrett, A. Ray, et al. Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cells Blood, December 15, 2008; 112(13): 5161 - 5170. [Abstract] [Full Text] [PDF] L. Bullinger, K. Dohner, R. Kranz, C. Stirner, S. Frohling, C. Scholl, Y. H. Kim, R. F. Schlenk, R. Tibshirani, H. Dohner, et al. An FLT3 gene-expression signature predicts clinical outcome in normal karyotype AML Blood, May 1, 2008; 111(9): 4490 - 4495. [Abstract] [Full Text] [PDF] E. Weisberg, L. Banerji, R. D. Wright, R. Barrett, A. Ray, D. Moreno, L. Catley, J. Jiang, E. Hall-Meyers, M. Sauveur-Michel, et al. Potentiation of antileukemic therapies by the dual PI3K/PDK-1 inhibitor, BAG956: effects on BCR-ABL- and mutant FLT3-expressing cells Blood, April 1, 2008; 111(7): 3723 - 3734. [Abstract] [Full Text] [PDF] R. W. Stam, M. L. den Boer, P. Schneider, M. Meier, H. B. Beverloo, and R. Pieters D-HPLC analysis of the entire FLT3 gene in MLL rearranged and hyperdiploid acute lymphoblastic leukemia Haematologica, November 1, 2007; 92(11): 1565 - 1568. [Abstract] [Full Text] [PDF] A. J. Mead, D. C. Linch, R. K. Hills, K. Wheatley, A. K. Burnett, and R. E. 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Serve AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations Blood, July 1, 2005; 106(1): 265 - 273. [Abstract] [Full Text] [PDF] R. Grundler, C. Miething, C. Thiede, C. Peschel, and J. Duyster FLT3-ITD and tyrosine kinase domain mutants induce 2 distinct phenotypes in a murine bone marrow transplantation model Blood, June 15, 2005; 105(12): 4792 - 4799. [Abstract] [Full Text] [PDF] T. Kindler, F. Breitenbuecher, S. Kasper, E. Estey, F. Giles, E. Feldman, G. Ehninger, G. Schiller, V. Klimek, S. D. Nimer, et al. Identification of a novel activating mutation (Y842C) within the activation loop of FLT3 in patients with acute myeloid leukemia (AML) Blood, January 1, 2005; 105(1): 335 - 340. [Abstract] [Full Text] [PDF]

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