title: ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia.
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.
authors: 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.
authors: Mark A
authors: 0000-0001-5587-4686
authors: MA
authors: Gregory
authors: Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, CO 80045; School of Medicine, University of Colorado, Aurora, CO 80045.
authors: Angelo
authors: A
authors: D'Alessandro
authors: School of Medicine, University of Colorado, Aurora, CO 80045; Integrated Department of Immunology, University of Colorado, Aurora, CO 80045.
authors: Francesca
authors: F
authors: Alvarez-Calderon
authors: School of Medicine, University of Colorado, Aurora, CO 80045; Department of Medicine, Division of Medical Oncology, University of Colorado, Aurora, CO 80045.
authors: Jihye
authors: J
authors: Kim
authors: Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, CO 80045; School of Medicine, University of Colorado, Aurora, CO 80045.
authors: Travis
authors: T
authors: Nemkov
authors: School of Medicine, University of Colorado, Aurora, CO 80045; Department of Medicine, Division of Hematology, University of Colorado, Aurora, CO 80045.
authors: Biniam
authors: B
authors: Adane
authors: Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, CO 80045; School of Medicine, University of Colorado, Aurora, CO 80045.
authors: Andrii I
authors: AI
authors: Rozhok
authors: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado, Aurora, CO 80045.
authors: Amit
authors: A
authors: Kumar
authors: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado, Aurora, CO 80045.
authors: Vijay
authors: V
authors: Kumar
authors: School of Medicine, University of Colorado, Aurora, CO 80045; Department of Medicine, Division of Hematology, University of Colorado, Aurora, CO 80045.
authors: Daniel A
authors: DA
authors: Pollyea
authors: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado, Aurora, CO 80045.
authors: Michael F
authors: MF
authors: Wempe
authors: School of Medicine, University of Colorado, Aurora, CO 80045; Department of Medicine, Division of Hematology, University of Colorado, Aurora, CO 80045.
authors: Craig T
authors: CT
authors: Jordan
authors: 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.
authors: Natalie J
authors: NJ
authors: Serkova
authors: 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.
authors: Aik Choon
authors: AC
authors: Tan
authors: Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, CO 80045; School of Medicine, University of Colorado, Aurora, CO 80045.
authors: Kirk C
authors: KC
authors: Hansen
authors: 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.
authors: James
authors: J
authors: DeGregori
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D052160:Benzothiazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004359:Drug Therapy, Combination; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016688:Mice, Inbred NOD; D008875:Middle Aged; D010084:Oxidation-Reduction; D010671:Phenylurea Compounds / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D006834:Hydrazines; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C512195:elesclomol; C544967:quizartinib; D005954:Glucosephosphate Dehydrogenase; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATM; FLT3; acute myeloid leukemia; glutathione; metabolism