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Proc Natl Acad Sci U S A. 2016 Oct 25;113(43):E6669-E6678. Epub 2016 Oct 10.

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

Author information

1
Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, CO 80045; School of Medicine, University of Colorado, Aurora, CO 80045; james.degregori@ucdenver.edu mark.gregory@ucdenver.edu.
2
Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, CO 80045; School of Medicine, University of Colorado, Aurora, CO 80045.
3
School of Medicine, University of Colorado, Aurora, CO 80045; Integrated Department of Immunology, University of Colorado, Aurora, CO 80045.
4
School of Medicine, University of Colorado, Aurora, CO 80045; Department of Medicine, Division of Medical Oncology, University of Colorado, Aurora, CO 80045.
5
School of Medicine, University of Colorado, Aurora, CO 80045; Department of Medicine, Division of Hematology, University of Colorado, Aurora, CO 80045.
6
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado, Aurora, CO 80045.
7
School of Medicine, University of Colorado, Aurora, CO 80045; Department of Anesthesiology, University of Colorado, Aurora, CO 80045; Department of Radiology, University of Colorado, Aurora, CO 80045.
8
School of Medicine, University of Colorado, Aurora, CO 80045; Department of Medicine, Division of Medical Oncology, University of Colorado, Aurora, CO 80045; Cancer Biology Program, University of Colorado, Aurora, CO 80045.
9
Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, CO 80045; School of Medicine, University of Colorado, Aurora, CO 80045; Integrated Department of Immunology, University of Colorado, Aurora, CO 80045; Cancer Biology Program, University of Colorado, Aurora, CO 80045; Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado, Aurora, CO 80045 james.degregori@ucdenver.edu mark.gregory@ucdenver.edu.

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.

KEYWORDS:

ATM; FLT3; acute myeloid leukemia; glutathione; metabolism

PMID:
27791036
PMCID:
PMC5086999
DOI:
10.1073/pnas.1603876113
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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