SEARCH:   Advanced

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 (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 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 Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 3, 2004 Accepted May 6, 2004 Identification and Characterization of a Novel Activating Mutation of the FLT3 Tyrosine Kinase in AML Jingrui Jiang, J G Paez, Jeffrey C Lee, Ronghai Bo, Richard M Stone, Daniel J DeAngelo, Irene Galinsky, Brian M Wolpin, Anna Jonasova, Paula Herman, Edward A Fox, Titus J Boggon, Michael J Eck, Ellen Weisberg, James D Griffin, D G Gilliland, Matthew Meyerson, and William R Sellers* Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Division of Hematology, Brigham and Women's Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA, USA Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Pathology, Harvard Medical School, Boston, MA, USA; The Broad Institute at Harvard and MIT, Cambridge, MA, USA Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; The Broad Institute at Harvard and MIT, Cambridge, MA, USA * Corresponding author; email: William_Sellers{at}dfci.harvard.edu. The FLT3 receptor is activated by juxtamembrane insertion mutations and by activation loop point mutations in patients with acute myeloblastic leukemia (AML). In a systematic tyrosine kinase gene exon resequencing study, 21 of the 24 FLT3 exons were sequenced in 53 AML, 9 ALL and 3 myelodysplasia samples. Three patients had novel point mutations at residue N841 resulting in a change to isoleucine in two samples and to tyrosine in one sample. Introduction of a FLT3-N841I cDNA into Ba/F3 cells led to IL3-independent proliferation, receptor phosphorylation, and constitutive activation of STAT5 and ERK kinases suggesting that the N841I mutation confers constitutive activity to the receptor. A FLT3 inhibitor (PKC412) inhibited the growth of Ba/F3-FLT3N841I cells (IC50 10 nM), but not of wild-type Ba/F3 cells cultured with IL3. PKC412 also reduced tyrosine phosphorylation of the mutant receptor and inhibited STAT5 phosphorylation. Examination of the FLT3 auto-inhibited 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. Gale FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia Blood, August 15, 2007; 110(4): 1262 - 1270. [Abstract] [Full Text] [PDF] E. Weisberg, A. L. Kung, R. D. Wright, D. Moreno, L. Catley, A. Ray, L. Zawel, M. Tran, J. Cools, G. Gilliland, et al. Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells Mol. Cancer Ther., July 1, 2007; 6(7): 1951 - 1961. [Abstract] [Full Text] [PDF] R. K. Thomas, B. Weir, and M. Meyerson Genomic approaches to lung cancer. Clin. Cancer Res., July 15, 2006; 12(14): 4384s - 4391s. [Abstract] [Full Text] [PDF] F. Heidel, F. K. Solem, F. Breitenbuecher, D. B. Lipka, S. Kasper, M. H. Thiede, C. Brandts, H. Serve, J. Roesel, F. Giles, et al. Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain Blood, January 1, 2006; 107(1): 293 - 300. [Abstract] [Full Text] [PDF] J. Jiang, H. Greulich, P. A. Janne, W. R. Sellers, M. Meyerson, and J. D. Griffin Epidermal Growth Factor-Independent Transformation of Ba/F3 Cells with Cancer-Derived Epidermal Growth Factor Receptor Mutants Induces Gefitinib-Sensitive Cell Cycle Progression Cancer Res., October 1, 2005; 65(19): 8968 - 8974. [Abstract] [Full Text] [PDF] S. Frohling, C. Scholl, D. G. Gilliland, and R. L. Levine Genetics of Myeloid Malignancies: Pathogenetic and Clinical Implications J. Clin. Oncol., September 10, 2005; 23(26): 6285 - 6295. [Abstract] [Full Text] [PDF] C. Choudhary, J. Schwable, C. Brandts, L. Tickenbrock, B. Sargin, T. Kindler, T. Fischer, W. E. Berdel, C. Muller-Tidow, and H. 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]

	Copyright © 2004 by American Society of Hematology         Online ISSN: 1528-0020