PuSH - Publication Server of Helmholtz Zentrum München: FLT3-ITD-TKD dual mutants associated with AML confer resistance to FLT3 PTK inhibitors and cytotoxic agents by overexpression of Bcl-x(L).

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Bagrintseva, K. ; Geisenhof, S. ; Kern, R. ; Eichenlaub, S. ; Reindl, C. ; Ellwart, J.W. ; Hiddemann, W. ; Spiekermann, K.

FLT3-ITD-TKD dual mutants associated with AML confer resistance to FLT3 PTK inhibitors and cytotoxic agents by overexpression of Bcl-x(L).

Blood 105, 3679-3685 (2005)

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FLT3 (fms-like tyrosine kinase 3) is constitu- tively activated in about 30% of patients with acute myeloid leukemia (AML) and repre- sents a disease-specific molecular marker. Although FLT3-LM (length mutation) and TKD (tyrosine kinase domain) mutations have been considered to be mutually exclu- sive, 1% to 2% of patients carry both muta- tions. However, the functional and clinical significance of this observation is unclear. We demonstrate that FLT3-ITD-TKD dual mu- tants induce drug resistance toward 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 (signal transducer and activator of transcrip- tion-5), leading to upregulation of Bcl-x(L) and RAD51 and arrest in the G 2 M 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 pheno- type in FLT3-ITD cells. The combination of rapamycin, a selective mTOR inhibitor, and FLT3 PTK inhibitors restored the drug sensi- tivity in FLT3 dual mutant–expressing cells. Our data provide the molecular basis for understanding clinical FLT3 PTK inhibitor resistance and point to therapeutical strate- gies to overcome drug resistance in pa- tients withAML.

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