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Blood, 15 March 2004, Vol. 103, No. 6, pp. 2266-2275.
Prepublished online as a Blood First Edition Paper on November 6, 2003; DOI 10.1182/blood-2003-05-1653.
Submitted May 22, 2003
Accepted October 20, 2003
Mutations in the tyrosine kinase domain of FLT3 define a new molecular mechanism of acquired drug resistance to PTK inhibitors in FLT3-ITD transformed hematopoietic cells
Ksenia Bagrintseva, Ruth Schwab, Tobias M Kohl, Susanne Schnittger, Sabine Eichenlaub, Joachim W Ellwart, Wolfgang Hiddemann, and Karsten Spiekermann*
Department of Medicine III, University Hospital Grosshadern, Ludwig-Maximilians University, Munich, Germany; Clinical Cooperative Group, GSF-National Research Center for Environment and Health, Munich, Germany
Institute of Molecular Immunology, GSF-National Research Center for Environment and Health, Munich, Germany
* Corresponding author; email: spiekermann{at}gsf.de.
Activating mutations in the juxtamembrane domain (FLT3-length mutations, FLT3-LM) and in the protein tyrosine kinase domain (TKD) of FLT3 (FLT3-TKD) represent the most frequent genetic alterations in acute myeloid leukemia (AML) and define a molecular target for therapeutical interventions by protein tyrosine kinase (PTK) inhibitors. We could show that distinct activating FLT3-TKD mutations at position D835 mediate primary resistance to FLT3 PTK inhibitors in FLT3 transformed cell lines. In the presence of increasing concentrations of the FLT3 PTK inhibitor SU5614 we generated inhibitor resistant Ba/F3 FLT3-internal tandem duplication (ITD) cell lines (Ba/F3 FLT3-ITD-R1-R4) that were characterized by a 7-26 fold higher IC50 to SU5614 compared to the parental ITD cells. The molecular characterization of ITD-R1-4 cells demonstrated that specific TKD mutations (D835N and Y842H) on the ITD background were acquired during selection with SU5614. Introduction of these dual ITD-TKD, but not single D835N or Y842H FLT3 mutants in Ba/F3 cells restored the FLT3 -inhibitor resistant phenotype. Our data show that pre-existing or acquired mutations in the PTK domain of FLT3 can induce drug resistance to FLT3 PTK inhibitors in vitro. These findings provide a molecular basis for the evaluation of clinical resistance to FLT3 PTK inhibitors in patients with AML.
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