title: Tyrosine kinase inhibition in leukemia induces an altered metabolic state sensitive to mitochondrial perturbations.
abstract: OBJECTIVE
  Although tyrosine kinase inhibitors (TKI) can be effective therapies for leukemia, they fail to fully eliminate leukemic cells and achieve durable remissions for many patients with advanced BCR-ABL(+) leukemias or acute myelogenous leukemia (AML). Through a large-scale synthetic lethal RNAi screen, we identified pyruvate dehydrogenase, the limiting enzyme for pyruvate entry into the mitochondrial tricarboxylic acid cycle, as critical for the survival of chronic myelogenous leukemia (CML) cells upon BCR-ABL inhibition. Here, we examined the role of mitochondrial metabolism in the survival of Ph(+) leukemia and AML upon TK inhibition.
  
  
  METHODS
  Ph(+) cancer cell lines, AML cell lines, leukemia xenografts, cord blood, and patient samples were examined.
  
  
  RESULTS
  We showed that the mitochondrial ATP-synthase inhibitor oligomycin-A greatly sensitized leukemia cells to TKI in vitro. Surprisingly, oligomycin-A sensitized leukemia cells to BCR-ABL inhibition at concentrations of 100- to 1,000-fold below those required for inhibition of respiration. Oligomycin-A treatment rapidly led to mitochondrial membrane depolarization and reduced ATP levels, and promoted superoxide production and leukemia cell apoptosis when combined with TKI. Importantly, oligomycin-A enhanced elimination of BCR-ABL(+) leukemia cells by TKI in a mouse model and in primary blast crisis CML samples. Moreover, oligomycin-A also greatly potentiated the elimination of FLT3-dependent AML cells when combined with an FLT3 TKI, both in vitro and in vivo.
  
  
  CONCLUSIONS
  TKI therapy in leukemia cells creates a novel metabolic state that is highly sensitive to particular mitochondrial perturbations. Targeting mitochondrial metabolism as an adjuvant therapy could therefore improve therapeutic responses to TKI for patients with BCR-ABL(+) and FLT3(ITD) leukemias.
authors.affiliation: Integrated Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado. School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Francesca
authors.initials: F
authors.lastname: Alvarez-Calderon
authors.affiliation: School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Gregory
authors.affiliation: School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Cancer Biology Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Catherine
authors.initials: C
authors.lastname: Pham-Danis
authors.affiliation: School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Pediatrics, Division of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Deborah
authors.initials: D
authors.lastname: DeRyckere
authors.affiliation: School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Medicine, Section of Hematology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Brett M
authors.initials: BM
authors.lastname: Stevens
authors.affiliation: School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Vadym
authors.initials: V
authors.lastname: Zaberezhnyy
authors.affiliation: School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Pediatrics, Division of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Amanda A
authors.initials: AA
authors.lastname: Hill
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Lelisa
authors.initials: L
authors.lastname: Gemta
authors.affiliation: School of Pharmacy, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.affiliation: School of Pharmacy, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Vijay
authors.initials: V
authors.lastname: Kumar
authors.affiliation: School of Pharmacy, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wempe
authors.affiliation: School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Medicine, Section of Hematology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Pollyea
authors.affiliation: School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Cancer Biology Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Medicine, Section of Hematology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Craig T
authors.initials: CT
authors.lastname: Jordan
authors.affiliation: School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Radiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Serkova
authors.affiliation: Integrated Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Cancer Biology Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Pediatrics, Division of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Medicine, Section of Hematology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Graham
authors.affiliation: Integrated Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Cancer Biology Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Pediatrics, Division of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Medicine, Section of Hematology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. James.DeGregori@ucdenver.edu.
authors.forename: James
authors.initials: J
authors.lastname: DeGregori
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D051047:Dihydrolipoyllysine-Residue Acetyltransferase / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D007658:Ketone Oxidoreductases / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics; D025261:Mitochondrial Proton-Translocating ATPases / Q000037:antagonists & inhibitors*; D009840:Oligomycins / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D034622:RNA Interference; D034741:RNA, Small Interfering; D013481:Superoxides / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D024101:Mitochondrial Proteins; D009840:Oligomycins; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C031004:oligomycin A; D013481:Superoxides; D000068877:Imatinib Mesylate; D007658:Ketone Oxidoreductases; C053164:pyruvate dehydrogenase (NADP+); D051047:Dihydrolipoyllysine-Residue Acetyltransferase; C494878:Dlat protein, mouse; C497971:Flt3 protein, mouse; D011505:Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D016044:Fusion Proteins, bcr-abl; D025261:Mitochondrial Proton-Translocating ATPases