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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: 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. 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