Abstract SY27-02: Exploring the significance of somatic mtDNA mutations in the context of acute leukemia

Abstract Somatic mitochondrial DNA (mtDNA) mutations are commonly observed in tumors, yet their functional role in pediatric cancers remains largely unexplored. The unique biology of mtDNA—including its heteroplasmic nature, where mutant and wild-type mtDNA coexist—poses challenges in understanding its contribution to disease progression. To address this, we utilized an integrative approach combining bulk whole-genome sequencing, single-cell analysis, and experimental modeling. Analysis of 637 matched tumor and germline samples from the Pediatric Cancer Genome Project revealed an enrichment of functional-impact mtDNA variants in specific pediatric leukemia subtypes. Single-cell sequencing of diagnostic leukemia samples demonstrated that somatic mtDNA mutations can emerge early in leukemogenesis and undergo positive selection, achieving intermediate heteroplasmy—a "sweet spot" balancing mitochondrial dysfunction and cellular fitness. Systems biology analyses linked these heteroplasmic mutations to functional heterogeneity and metabolic adaptability within leukemic cells. To directly investigate the role of mtDNA mutations in leukemogenesis, we studied hematopoietic progenitor cells (HPCs) with varying mtDNA mutation burdens using wild-type, heterozygous, and homozygous mtDNA mutator mice (Polg D257A). Heterozygous Polg HPCs exhibited a higher incidence of spontaneous leukemogenesis and supported oncogene-driven transformation, whereas homozygous Polg HPCs showed impaired leukemogenesis due to disrupted glucose metabolism and pyruvate dehydrogenase inhibition. These findings highlight the role of intermediate heteroplasmy in balancing mitochondrial dysfunction and cellular fitness, enabling leukemic cells to maintain metabolic adaptability. Targeting this balance may uncover novel therapeutic strategies to disrupt the metabolic plasticity driving pediatric leukemia progression. Citation Format: Mondira Kundu. Exploring the significance of somatic mtDNA mutations in the context of acute leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY27-02.