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Blood, 1 May 2005, Vol. 105, No. 9, pp. 3679-3685.
Prepublished online as a Blood First Edition Paper on December 30, 2004; DOI 10.1182/blood-2004-06-2459.
 Previous Article | Next Article 
Submitted June 29, 2004
Accepted November 12, 2004
FLT3-ITD-TKD dual mutants associated with Acute Myeloid Leukemia (AML) confer resistance to FLT3 PTK inhibitors and cytotoxic agents by overexpression of Bcl-x(L)
Ksenia Bagrintseva, Stefanie Geisenhof, Ruth Kern, Sabine Eichenlaub, Carola Reindl, Joachim W Ellwart, Wolfgang Hiddemann, and Karsten Spiekermann*
Department of Medicine III, University Hospital Grosshadern, Ludwig-Maximilians University, Clinical Cooperative Group 'Leukemia', Munich, Germany
Institute of Molecular Immunology, GSF-National Research Center for Environment and Health, Munich, Germany
* Corresponding author; email: k.spiekermann{at}gmx.de.
FLT3 (fms-like tyrosine kinase 3) is constitutively activated in about 30% of patients with acute myeloid leukemia (AML) and represents a disease specific molecular marker. Although FLT3 length mutations (LM) and tyrosine kinase domain (TKD) mutations have been considered to be mutually exclusive, 1-2% of patients carry both mutations. However, the functional and clinical significance of this observation is unclear.
We demonstrate that FLT3-LM+TKD dual mutants induce drug resistance towards PTK inhibitors and cytotoxic agents in in vitro model systems. As molecular mechanisms of resistance we found that FLT3-ITD/TKD mutants cause hyperactivation of STAT5 and its target genes Bcl-x(L) and RAD51 and arrest in G2M phase of the cell cycle. Overexpression of Bcl-x(L) was identified as the critical mediator of drug resistance and recapitulates the PTK inhibitor and daunorubicin resistant phenotype in FLT3-ITD cells. The combination of rapamycin, a selective mTOR inhibitor and FLT3 PTK inhibitors restored the drug sensitivity in FLT3 dual mutant expressing cells.
Our data provide the molecular basis for understanding clinical FLT3 PTK inhibitor resistance and point to therapeutical strategies to overcome drug resistance in patients with AML.
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