Mitochondrial DNA Mutations Determine Favourable Molecular Responses to Targeted Kinase Inhibitor Therapy and Impair Oxidative Phosphorylation
Year: 2025
Type: preprint
Study design: Observational Study
Abstract: Somatic mutations in mitochondrial DNA (mtDNA) are not typically considered key oncogenic drivers of cancer, primarily because of a high synonymous to non-synonymous variant ratio. Here, we surveyed 248 matched diagnosis and remission samples from patients with chronic myeloid leukemia (CML) and found a 75% had mitochondrial mutations with a median number of 2 mutations per patient. mtDNA mutations were predominantly non-synonymous, enriched in the D-loop control region, and likely originated from replication and transcriptional errors. Functionally, mtDNA mutations were associated with reduced oxidative phosphorylation (OXPHOS), as measured by Seahorse analyser. This metabolic vulnerability could be phenocopied by treatment with the complex I inhibitor IACS-10759 in combination with the targeted tyrosine kinase inhibitor (TKI) imatinib, which significantly reduced the colony-forming potential of TKI resistant leukemic stem/progenitor cells (LSPCs). Strikingly, we show that mtDNA mutations were associated with increased sensitivity to imatinib therapy in the clinic. Patients with ≥3 mutations and patients with mutations in the D-loop showed significantly higher cumulative incidence of major molecular response at 24 months (90% vs. 68%, p = 0.004, and 89% vs 68%, p = 0.004 respectively). Single-cell RNA sequencing further revealed enrichment in non-synonymous mtDNA variants in LSPCs from TKI-sensitive patients, while TKI-resistant cells exhibited upregulated gene signatures related to glycerolipid and phospholipid metabolism and mitochondrial biogenesis. Together, our findings demonstrate that mtDNA mutations are key determinants of sensitivity to targeted therapy, rather than oncogenic drivers of leukemogenesis. Mechanistically, non-synonymous mtDNA mutations appear to restrict mitochondrial metabolic plasticity, with widespread implications for precision oncology.
Authors: Ilaria S Pagani, Vaidehi Krishnan, Ouyang Fengcong John, Chung H Kok, BeiJun Chen, Kian Leong Lee, Cong M Pham, Paul Wang, Elyse Page, Phuong Dang, Verity A Saunders, Jane James, Kelly Lim, Naranie Shanmuganathan, Agnes Yong, Susan Branford, Charles Chuah, David T Yeung, Deborah White, G. Vignir Helgason, Daniel Thomas, Sin Tiong Ong, Timothy P Hughes, David M Ross
Institutions: South Australian Health and Medical Research Institute, Australasian Leukaemia and Lymphoma Group, The University of Adelaide, National University of Singapore, Duke-NUS Medical School, University of South Australia, Centre for Cancer Biology, Walter and Eliza Hall Institute of Medical Research, The University of Western Australia, Royal Perth Hospital, Singapore General Hospital, National Cancer Centre Singapore, University of Glasgow, Flinders University
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4415769874