ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

Mark A. Gregory, Angelo D'Alessandro, Francesca Alvarez-Calderon, Jihye Kim, Travis Nemkov, Biniam Adane, Andrii I. Rozhok, Amit Kumar, Vijay Kumar, Daniel A. Pollyea, Michael F. Wempe, Craig T. Jordan, Natalie J. Serkova, Aik Choon Tan, Kirk C. Hansen, James DeGregori

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29 Citations (Scopus)

Abstract

Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and drive leukemic cell growth and survival. Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interference (RNAi)-based screen that identified ATM (ataxia telangiectasia mutated) as being synthetic lethal with FLT3 inhibitor therapy.We found that inactivating ATM or its downstream effector glucose 6-phosphate dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis. Examination of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in central carbon metabolism, resulting in impaired production of the antioxidant factor glutathione, which was further impaired by ATM or G6PD inactivation. Moreover, FLT3 inhibition elicited severe mitochondrial oxidative stress that is causative in apoptosis and is exacerbated by ATM/G6PD inhibition. The use of an agent that intensifies mitochondrial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vitro and in vivo, revealing a therapeutic strategy for the improved treatment of FLT3 mutated AML.

Original languageEnglish
Pages (from-to)E6669-E6678
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number43
DOIs
Publication statusPublished - 2016 Oct 25

Keywords

  • ATM
  • Acute myeloid leukemia
  • FLT3
  • Glutathione
  • Metabolism

ASJC Scopus subject areas

  • General

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    Gregory, M. A., D'Alessandro, A., Alvarez-Calderon, F., Kim, J., Nemkov, T., Adane, B., Rozhok, A. I., Kumar, A., Kumar, V., Pollyea, D. A., Wempe, M. F., Jordan, C. T., Serkova, N. J., Tan, A. C., Hansen, K. C., & DeGregori, J. (2016). ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia. Proceedings of the National Academy of Sciences of the United States of America, 113(43), E6669-E6678. https://doi.org/10.1073/pnas.1603876113