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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 (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 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  |  Next Article  Submitted November 29, 2007 Accepted December 9, 2008 A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in acute myeloid leukemia Frank Breitenbuecher, Boyka Markova, Stefan Kasper, Birgit Carius, Torsten Stauder, Frank D. Bohmer, Kristina Masson, Lars Ronnstrand, Christoph Huber, Thomas Kindler, and Thomas Fischer* 3rd Medical Department, Johannes Gutenberg-University, Mainz, Germany Department of Medicine (Cancer Research), West German Cancer Center, University Hospital Essen, Essen, Germany Institute of Molecular Cell Biology, University of Jena, Jena, Germany Experimental Clinical Chemistry, Department of Laboratory Medicine, Lund University, Malmo University Hospital, Malmo, Sweden Department of Hematology/Oncology, Medical Center, Otto-von-Guericke University Magdeburg, Magdeburg, Germany * Corresponding author; email: thomas.fischer{at}med.ovgu.de. 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 harbouring internal tandem duplications (ITD) 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: a FLT3 receptor harbouring a non-juxtamembrane ITD atypically integrating into the -2 sheet of the first kinase domain (FLT3_ITD627E) induces dramatic up-regulation of the anti-apoptotic protein MCL-1. Using RNA interference technology, de-regulated 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 upregulation 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 suggests 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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