ArticleBlood2017
Leveraging increased cytoplasmic nucleoside kinase activity to target mtDNA and oxidative phosphorylation in AML.
Article in Blood, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
47 citing papers in PubMed, 1 synthesis or guideline pooled it, 72 citations in OpenAlex.
- Targeting Mitochondrial Oxidative Phosphorylation Eradicates Acute Myeloid Leukemic Stem Cells.Frontiers in oncology · 2022Pooled it
- The STAT3-VDAC1 axis modulates mitochondrial function and plays a critical role in the survival of acute myeloid leukemia cells.Haematologica · 2026Article
- Zalcitabine induces ferroptosis in multiple myeloma through the TFAM-cGAS-STING-SLC7A11 axis.Journal of translational medicine · 2026Article
- Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity.Science (New York, N.Y.) · 2026Article
- ALKBH1 Drives Tumorigenesis and Drug Resistance via tRNA-decoding Reprogramming and Codon-biased Translation.Cancer discovery · 2025Article
- Metabolic Signature ofJournal of personalized medicine · 2025Review
- High tide or low tide: the transport and metabolism of mitochondrial nucleotides.The Biochemical journal · 2025Review
- Mitochondrial metabolism and cancer therapeutic innovation.Signal transduction and targeted therapy · 2025Review
- Article
- Deregulation of mitochondrial gene expression in cancer: mechanisms and therapeutic opportunities.British journal of cancer · 2024Review
- Our current understanding of the biological impact of endometrial cancer mtDNA genome mutations and their potential use as a biomarker.Frontiers in oncology · 2024Review
- MYC-driven increases in mitochondrial DNA copy number occur early and persist throughout prostatic cancer progression.JCI insight · 2023Article
- The role of bone marrow microenvironment (BMM) cells in acute myeloid leukemia (AML) progression: immune checkpoints, metabolic checkpoints, and signaling pathways.Cell communication and signaling : CCS · 2023Review
- A Leukemic Target with a Thousand Faces: The Mitochondria.International journal of molecular sciences · 2023Review
- Review
- Structural and Molecular Basis for Mitochondrial DNA Replication and Transcription in Health and Antiviral Drug Toxicity.Molecules (Basel, Switzerland) · 2023Review
- FUNDC1 protects against doxorubicin-induced cardiomyocyte PANoptosis through stabilizing mtDNA via interaction with TUFM.Cell death & disease · 2022Article
- Article
- Fluorescence Imaging of Mitochondrial DNA Base Excision Repair Reveals Dynamics of Oxidative Stress Responses.Angewandte Chemie (International ed. in English) · 2022Article
- Article
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Authors and funding
17 authors at 4 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.