Abstract
Acute myeloid leukemia (AML) cells carry molecular defects that promote their leukemic proliferation, resistance to apoptosis and defect in differentiation. Pharmacological targeting of the nuclear factor kappaB (NF-κB) pathway has been shown to promote apoptosis of primary AML cells and to sensitize blasts to neoplastic drugs (Frelin, Blood 2005, 105, 804). The Fms-like tyrosine kinase 3 (FLT3), which sustains proliferation of normal hematopoietic progenitors is frequently overexpressed or mutated in AML patients. Using Ba/F3 murine pre-B cells transfected with various mutants of FLT3 (ITD, D835V, D835Y) and the MV4-11 human AML line, we show that normal or oncogenic stimulation of FLT3 led to activation of NF-κB. Pharmacological inhibition of either FLT3 with AG1296 or NF-κB with the small molecule inhibitor of IkappaB kinase-2 AS602868 reduced viability and triggered cell death. Moreover, AS602868 was also found to interfere directly with FLT3 kinase activation. AS602868 thus appears to target two different kinases that play a crucial role in the pathogenesis of AML, making it particularly attractive as a new therapeutical approach for AML.
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Acknowledgements
We thank Mrs Pascale Gaillard (Merck Serono) and Laura Liu (EMB-Serono) for their help with FLT3 experiments. This work was supported by institutional funding from INSERM, by grants from ARC, La Fondation de France comité leucémies and Merck Serono International SA.
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Griessinger, E., Imbert, V., Lagadec, P. et al. AS602868, a dual inhibitor of IKK2 and FLT3 to target AML cells. Leukemia 21, 877–885 (2007). https://doi.org/10.1038/sj.leu.2404614
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DOI: https://doi.org/10.1038/sj.leu.2404614
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