SEARCH:   Advanced

Blood, 1 January 2005, Vol. 105, No. 1, pp. 335-340. Prepublished online as a Blood First Edition Paper on September 2, 2004; DOI 10.1182/blood-2004-02-0660. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-02-0660v1 105/1/335    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 Kindler, T. Articles by Fischer, T. Search for Related Content PubMed PubMed Citation Articles by Kindler, T. Articles by Fischer, T. Related Collections Neoplasia Oncogenes and Tumor Suppressors Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Identification of a novel activating mutation (Y842C) within the activation loop of FLT3 in patients with acute myeloid leukemia (AML) Thomas Kindler, Frank Breitenbuecher, Stefan Kasper, Eli Estey, Francis Giles, Eric Feldman, Gerhard Ehninger, Gary Schiller, Virginia Klimek, Stephen D. Nimer, Alois Gratwohl, Chuna Ram Choudhary, Constan Mueller-Tidow, Hubert Serve, Harald Gschaidmeier, Pamela S. Cohen, Christoph Huber, and Thomas Fischer From the Johannes-Gutenberg University of Mainz, 3rd Medical Department, Mainz, Germany; MD Anderson Cancer Center (MDACC), Houston, TX; Cornell University Cancer Center, New York, NY; Carl Gustav Carus University, Dresden, Germany; UCLA Medical Center, Los Angeles, CA; Memorial Sloan Kettering Cancer Center, New York, NY; University of Basel, Basel, Switzerland; University of Muenster, Department of Medicine, Hematology/Oncology, Muenster, Germany; Novartis Pharmaceuticals, Nuernberg, Germany; and Novartis Oncology, East Hanover, NJ. Fms-like tyrosine kinase 3 (FLT3) receptor mutations as internal tandem duplication (ITD) or within the kinase domain are detected in up to 35% of patients with acute myeloid leukemia (AML). N-benzoyl staurosporine (PKC412), a highly effective inhibitor of mutated FLT3 receptors, has significant antileukemic efficacy in patients with FLT3-mutated AML. Mutation screening of FLT3 exon 20 in AML patients (n = 110) revealed 2 patients with a novel mutation (Y842C) within the highly conserved activation loop of FLT3. FLT3-Y842C-transfected 32D cells showed constitutive FLT3 tyrosine phosphorylation and interleukin 3 (IL-3)-independent growth. Treatment with PKC412 led to inhibition of proliferation and apoptotic cell death. Primary AML blasts bearing FLT3-Y842C mutations showed constitutive FLT3 and signal transducer and activator of transcription 5 (STAT-5) tyrosine phosphorylation. Ex vivo PKC412 treatment of primary blasts resulted in suppression of constitutive FLT3 and STAT-5 activation and apoptotic cell death. Inspection of the FLT3 structure revealed that Y842 is the key residue in regulating the switch from the closed to the open (= active) conformation of the FLT3 activation loop. Overall, our data suggest that mutations at Y842 represent a significant new activating mutation in AML blasts. Since FLT3 tyrosine kinase inhibitors (TKIs) such as PKC412 are currently being investigated in clinical trials in AML, extended sequence analysis of FLT3 may be helpful in defining the spectrum of TKI-sensitive FLT3 mutations in AML. (Blood. 2005;105:335-340) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. Briesewitz Fathoming Flt3 Blood, April 23, 2009; 113(17): 3889 - 3890. [Full Text] [PDF] F. Breitenbuecher, S. Schnittger, R. Grundler, B. Markova, B. Carius, A. Brecht, J. Duyster, T. Haferlach, C. Huber, and T. Fischer Identification of a novel type of ITD mutations located in nonjuxtamembrane domains of the FLT3 tyrosine kinase receptor Blood, April 23, 2009; 113(17): 4074 - 4077. [Abstract] [Full Text] [PDF] F. Breitenbuecher, B. Markova, S. Kasper, B. Carius, T. Stauder, F. D. Bohmer, K. Masson, L. Ronnstrand, C. Huber, T. Kindler, et al. A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML Blood, April 23, 2009; 113(17): 4063 - 4073. [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] T. Kindler, M. G. Cornejo, C. Scholl, J. Liu, D. S. Leeman, J. E. Haydu, S. Frohling, B. H. Lee, and D. G. Gilliland K-RasG12D-induced T-cell lymphoblastic lymphoma/leukemias harbor Notch1 mutations and are sensitive to {gamma}-secretase inhibitors Blood, October 15, 2008; 112(8): 3373 - 3382. [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] U. Bacher, C. Haferlach, W. Kern, T. Haferlach, and S. Schnittger Prognostic relevance of FLT3-TKD mutations in AML: the combination matters--an analysis of 3082 patients Blood, March 1, 2008; 111(5): 2527 - 2537. [Abstract] [Full Text] [PDF] S. P. Whitman, A. S. Ruppert, M. D. Radmacher, K. Mrozek, P. Paschka, C. Langer, C. D. Baldus, J. Wen, F. Racke, B. L. Powell, et al. FLT3 D835/I836 mutations are associated with poor disease-free survival and a distinct gene-expression signature among younger adults with de novo cytogenetically normal acute myeloid leukemia lacking FLT3 internal tandem duplications Blood, February 1, 2008; 111(3): 1552 - 1559. [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] H. Schepers, D. van Gosliga, A. T. J. Wierenga, B. J. L. Eggen, J. J. Schuringa, and E. Vellenga STAT5 is required for long-term maintenance of normal and leukemic human stem/progenitor cells Blood, October 15, 2007; 110(8): 2880 - 2888. [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] S. Vempati, C. Reindl, S. K. Kaza, R. Kern, T. Malamoussi, M. Dugas, G. Mellert, S. Schnittger, W. Hiddemann, and K. Spiekermann Arginine 595 is duplicated in patients with acute leukemias carrying internal tandem duplications of FLT3 and modulates its transforming potential Blood, July 15, 2007; 110(2): 686 - 694. [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] D. B. Shankar, J. Li, P. Tapang, J. Owen McCall, L. J. Pease, Y. Dai, R.-Q. Wei, D. H. Albert, J. J. Bouska, D. J. Osterling, et al. ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia Blood, April 15, 2007; 109(8): 3400 - 3408. [Abstract] [Full Text] [PDF] C. Graf, F. Heidel, S. Tenzer, M. P. Radsak, F. K. Solem, C. M. Britten, C. Huber, T. Fischer, and T. Wolfel A neoepitope generated by an FLT3 internal tandem duplication (FLT3-ITD) is recognized by leukemia-reactive autologous CD8+ T cells Blood, April 1, 2007; 109(7): 2985 - 2988. [Abstract] [Full Text] [PDF] C. Reindl, K. Bagrintseva, S. Vempati, S. Schnittger, J. W. Ellwart, K. Wenig, K.-P. Hopfner, W. Hiddemann, and K. Spiekermann Point mutations in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML Blood, May 1, 2006; 107(9): 3700 - 3707. [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] F. Giles, S. Verstovsek, D. Thomas, S. Gerson, J. Cortes, S. Faderl, A. Ferrajoli, F. Ravandi, S. Kornblau, G. Garcia-Manero, et al. Phase I Study of Cloretazine (VNP40101M), a Novel Sulfonylhydrazine Alkylating Agent, Combined with Cytarabine in Patients with Refractory Leukemia Clin. Cancer Res., November 1, 2005; 11(21): 7817 - 7824. [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]

	Copyright © 2005 by American Society of Hematology         Online ISSN: 1528-0020