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Apoptosis

BH3 mimetic ABT-737 neutralizes resistance to FLT3 inhibitor treatment mediated by FLT3-independent expression of BCL2 in primary AML blasts

Leukemia volume 21, pages 1763–1772 (2007)Cite this article

Abstract

FLT3 defines a promising target for the treatment of acute myeloid leukemia (AML). In contrast to their efficacy in cell lines, FLT3-specific inhibitors as single agents have only modest clinical activity in patients with AML. As demonstrated here, overexpression of anti-apoptotic proteins of the BCL2 family leads to resistance against FLT3 inhibitors in a hematopoietic cell line model with activating FLT3 mutations. The susceptibility to FLT3 inhibition could be restored by treatment with the novel BH3 mimetic ABT-737. Primary AML samples tested in our study showed a high expression of BCL2 protein, but not of BCL-xL or MCL1. BCL2 protein levels were not reduced after dephosphorylation of FLT3 and its downstream target STAT5 in patient samples with FLT3 internal tandem duplications. Interestingly, treatment with ABT-737 caused apoptotic cell death in all primary AML samples at submicromolar level and synergized efficiently with FLT3 inhibition in AML samples with activating FLT3 mutations. In contrast to AML cell lines, BCR-ABL transformed human cells showed resistance to ABT-737, which might be due to the induction of MCL1 by BCR-ABL. Inhibition of BCL2 family members might define a novel highly efficient and specific strategy in the combined or monotreatment of AML.

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Acknowledgements

We thank Evelyn Zellmeier, Gudrun Mellert, Elke Habben and Belay Tizazu for excellent technical assistance in Ficoll separation of primary samples and Dres. Christina Schessl, Grit Hutter, Harald Ehrhard, Philipp Greif, Vijay Rawat, and Marc Weinkauf for helpful discussions. We also thank Abbott Laboratories for providing ABT-737 and ABT control substance. This study was supported in part by a grant from the ‘NOVARTIS-STIFTUNG FÜR THERAPEUTISCHE FORSCHUNG’.

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Authors and Affiliations

  1. Department of Internal Medicine III, Clinical Cooperative Group ‘Leukemia’, University Hospital Grosshadern, Ludwig-Maximilians University, GSF-National Research Center for Environment and Health, Munich, Germany

    T M Kohl, C Hellinger, F Ahmed, C Buske, W Hiddemann, S K Bohlander & K Spiekermann

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  1. T M Kohl
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  2. C Hellinger
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Correspondence to T M Kohl.

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Supplementary Information accompanies the paper on the Leukemia Web site (http://www.nature.com/leu)

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Kohl, T., Hellinger, C., Ahmed, F. et al. BH3 mimetic ABT-737 neutralizes resistance to FLT3 inhibitor treatment mediated by FLT3-independent expression of BCL2 in primary AML blasts. Leukemia 21, 1763–1772 (2007). https://doi.org/10.1038/sj.leu.2404776

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