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Leveraging increased cytoplasmic nucleoside kinase activity to target mtDNA and oxidative phosphorylation in AML
- Source :
- Blood. 129:2657-2666
- Publication Year :
- 2017
- Publisher :
- American Society of Hematology, 2017.
-
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.
- Subjects :
- DNA Replication
0301 basic medicine
Immunology
Mice, SCID
Mitochondrion
Biology
DNA, Mitochondrial
Biochemistry
Oxidative Phosphorylation
03 medical and health sciences
chemistry.chemical_compound
Cell Line, Tumor
hemic and lymphatic diseases
Tumor Cells, Cultured
Animals
Humans
Cells, Cultured
Nucleoside-phosphate kinase
integumentary system
Zalcitabine
Kinase
Phosphotransferases
Cytidine
Cell Biology
Hematology
NM23 Nucleoside Diphosphate Kinases
Molecular biology
Leukemia, Myeloid, Acute
030104 developmental biology
chemistry
Cell culture
Signal transduction
Stem cell
Nucleoside-Phosphate Kinase
Nucleoside
Signal Transduction
Subjects
Details
- ISSN :
- 15280020 and 00064971
- Volume :
- 129
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....a03ddb39984d3b6f5bdfce69409af1bc