title: Leveraging increased cytoplasmic nucleoside kinase activity to target mtDNA and oxidative phosphorylation in AML.
abstract: Mitochondrial DNA (mtDNA) biosynthesis requires replication factors and adequate nucleotide pools from the mitochondria and cytoplasm. We performed gene expression profiling analysis of 542 human acute myeloid leukemia (AML) samples and identified 55% with upregulated mtDNA biosynthesis pathway expression compared with normal hematopoietic cells. Genes that support mitochondrial nucleotide pools, including mitochondrial nucleotide transporters and a subset of cytoplasmic nucleoside kinases, were also increased in AML compared with normal hematopoietic samples. Knockdown of cytoplasmic nucleoside kinases reduced mtDNA levels in AML cells, demonstrating their contribution in maintaining mtDNA. To assess cytoplasmic nucleoside kinase pathway activity, we used a nucleoside analog 2'3'-dideoxycytidine (ddC), which is phosphorylated to the activated antimetabolite, 2'3'-dideoxycytidine triphosphate by cytoplasmic nucleoside kinases. ddC is a selective inhibitor of the mitochondrial DNA polymerase γ. ddC was preferentially activated in AML cells compared with normal hematopoietic progenitor cells. ddC treatment inhibited mtDNA replication, oxidative phosphorylation, and induced cytotoxicity in a panel of AML cell lines. Furthermore, ddC preferentially inhibited mtDNA replication in a subset of primary human leukemia cells and selectively targeted leukemia cells while sparing normal progenitor cells. In animal models of human AML, treatment with ddC decreased mtDNA, electron transport chain proteins, and induced tumor regression without toxicity. ddC also targeted leukemic stem cells in secondary AML xenotransplantation assays. Thus, AML cells have increased cytidine nucleoside kinase activity that regulates mtDNA biogenesis and can be leveraged to selectively target oxidative phosphorylation in AML.
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.|Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: Sanduni U
authors.initials: SU
authors.lastname: Liyanage
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Rose
authors.initials: R
authors.lastname: Hurren
authors.affiliation: Donnelly Centre for Cellular and Biomolecular Research, Toronto, ON, Canada.
authors.forename: Veronique
authors.initials: V
authors.lastname: Voisin
authors.affiliation: Goodman Cancer Research Centre, Metabolomics Core Facility, McGill University, Montreal, QC, Canada; and.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Bridon
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wang
authors.affiliation: Donnelly Centre for Cellular and Biomolecular Research, Toronto, ON, Canada.
authors.forename: ChangJiang
authors.initials: C
authors.lastname: Xu
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Neil
authors.initials: N
authors.lastname: MacLean
authors.affiliation: Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: Thirushi P
authors.initials: TP
authors.lastname: Siriwardena
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Marcela
authors.initials: M
authors.lastname: Gronda
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Dana
authors.initials: D
authors.lastname: Yehudai
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Shrivani
authors.initials: S
authors.lastname: Sriskanthadevan
authors.affiliation: Goodman Cancer Research Centre, Metabolomics Core Facility, McGill University, Montreal, QC, Canada; and.
authors.forename: Daina
authors.initials: D
authors.lastname: Avizonis
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Aisha
authors.initials: A
authors.lastname: Shamas-Din
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.affiliation: Donnelly Centre for Cellular and Biomolecular Research, Toronto, ON, Canada.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Bader
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Laposa
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004261:DNA Replication; D004272:DNA, Mitochondrial / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D016513:Mice, SCID; D054778:NM23 Nucleoside Diphosphate Kinases / Q000378:metabolism; D009703:Nucleoside-Phosphate Kinase / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D016047:Zalcitabine / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D054778:NM23 Nucleoside Diphosphate Kinases; D016047:Zalcitabine; D010770:Phosphotransferases; C021892:nucleoside phosphotransferase; D009703:Nucleoside-Phosphate Kinase; C517938:NME1 protein, human; C517940:NME2 protein, human