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Blood, 23 April 2009, Vol. 113, No. 17, pp. 4063-4073. Prepublished online as a Blood First Edition Paper on January 14, 2009; DOI 10.1182/blood-2007-11-126664. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-11-126664v1 113/17/4063    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 Breitenbuecher, F. Articles by Fischer, T. Search for Related Content PubMed PubMed Citation Articles by Breitenbuecher, F. Articles by Fischer, T. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML Frank Breitenbuecher1, Boyka Markova1, Stefan Kasper1, Birgit Carius1, Torsten Stauder1, Frank D. Böhmer2, Kristina Masson3, Lars Rönnstrand3, Christoph Huber1, Thomas Kindler1,*, and Thomas Fischer1,* 1 3rd Medical Department, Johannes Gutenberg-University, Mainz, Germany; 2 Institute of Molecular Cell Biology, University of Jena, Jena, Germany; and 3 Experimental Clinical Chemistry, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden Currently, FLT3 tyrosine kinase inhibitors (TKIs) are emerging as the most promising drug therapy to overcome the dismal prognosis of acute myelogenous leukemia (AML) patients harboring internal tandem duplications (ITDs) of FLT3. However, up-front drug resistance occurs in approximately 30% of patients, and molecular mechanisms of resistance are poorly understood. Here, we have uncovered a novel mechanism of primary resistance to FLT3 TKIs in AML: an FLT3 receptor harboring a nonjuxtamembrane ITD atypically integrating into the β-2 sheet of the first kinase domain (FLT3_ITD627E) induces dramatic up-regulation of the anti-apoptotic myeloid cell leukemia 1 protein (MCL-1). Using RNA interference technology, deregulated MCL-1 protein expression was shown to play a major role in conferring the resistance phenotype of 32D_ITD627E cells. Enhanced and sustained binding of the adaptor protein GRB-2 to the FLT3_ITD627E receptor is involved in MCL-1 up-regulation and is independent from TKI (PKC412)–induced inhibition of the receptor kinase. Thus, we describe a new mechanism of primary resistance to TKIs, which operates by reprogramming local and distant signal transduction events of the FLT3 tyrosine kinase. The data presented suggest that particular ITDs of FLT3 may be associated with rewired signaling and differential responsiveness to TKIs. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Fathoming Flt3 Roger Briesewitz Blood 2009 113: 3889-3890. [Full Text] [PDF] This article has been cited by other articles: S. Kayser, R. F. Schlenk, M. C. Londono, F. Breitenbuecher, K. Wittke, J. Du, S. Groner, D. Spath, J. Krauter, A. Ganser, et al. Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome Blood, September 17, 2009; 114(12): 2386 - 2392. [Abstract] [Full Text] [PDF] R. Briesewitz Fathoming Flt3 Blood, April 23, 2009; 113(17): 3889 - 3890. [Full Text] [PDF]

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