Molecular targets for therapy

ITD mutation in FLT3 tyrosine kinase promotes Warburg effect and renders therapeutic sensitivity to glycolytic inhibition

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Abstract

Internal tandem duplication (ITD) mutation in Fms-like tyrosine kinase 3 gene (FLT3/ITD) represents an unfavorable genetic change in acute myeloid leukemia (AML) and is associated with poor prognosis. Metabolic alterations have been involved in tumor progression and attracted interest as a target for therapeutic intervention. However, few studies analyzed the adaptations of cellular metabolism in the context of FLT3/ITD mutation. Here, we report that FLT3/ITD causes a significant increase in aerobic glycolysis through AKT-mediated upregulation of mitochondrial hexokinase (HK2), and renders the leukemia cells highly dependent on glycolysis and sensitive to pharmacological inhibition of glycolytic activity. Inhibition of glycolysis preferentially causes severe ATP depletion and massive cell death in FLT3/ITD leukemia cells. Glycolytic inhibitors significantly enhances the cytotoxicity induced by FLT3 tyrosine kinase inhibitor sorafenib. Importantly, such combination provides substantial therapeutic benefit in a murine model bearing FLT3/ITD leukemia. Our study suggests that FLT3/ITD mutation promotes Warburg effect, and such metabolic alteration can be exploited to develop effective therapeutic strategy for treatment of AML with FLT3/ITD mutation via metabolic intervention.

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Acknowledgements

We thank Dr Donald Small for providing the BaF3/ITD cells. The current study was supported by Guangdong Natural Science Foundation (No. 2014A030313037), National Basic Research Program of China (973 program, No. 2013CB910304), Guangzhou Innovation Research Program (LCY201317) and Guangzhou Technology Program (No. 201508020250).

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Correspondence to G Garcia-Manero or P Huang or Y Hu.

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The authors declare no conflict of interest.

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Supplementary Information accompanies this paper on the Leukemia website

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Ju, H., Zhan, G., Huang, A. et al. ITD mutation in FLT3 tyrosine kinase promotes Warburg effect and renders therapeutic sensitivity to glycolytic inhibition. Leukemia 31, 2143–2150 (2017) doi:10.1038/leu.2017.45

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