Metformin reduces the competitive advantage of Dnmt3aR878H HSPCs

• 成果类型: Article
• 署名作者: Hosseini, Mohsen; Voisin, Veronique; Chegini, Ali; Varesi, Angelica; Cathelin, Severine; Ayyathan, Dhanoop Manikoth; Liu, Alex C. H.; Yang, Yitong; Wang, Vivian; Maher, Abdula; Grignano, Eric; Reisz, Julie A.; D'Alessandro, Angelo; Young, Kira; Wu, Yiyan; Fiumara, Martina; Ferrari, Samuele; Naldini, Luigi; Gaiti, Federico; Pai, Shraddha; Egan, Grace; Schimmer, Aaron D.; Bader, Gary D.; Dick, John E.; Xie, Stephanie Z.; Trowbridge, Jennifer J.; Chan, Steven M.
• 署名单位: University of Toronto; University Health Network Toronto; Princess Margaret Cancer Centre; University of Toronto; University of Toronto; University of Toronto; University of Colorado System; University of Colorado Anschutz Medical Campus; Jackson Laboratory; Vita-Salute San Raffaele University; IRCCS Ospedale San Raffaele; Fondazione Telethon; San Raffaele Telethon Institute For Gene Therapy (Sr-Tiget); Vita-Salute San Raffaele University; University of Toronto; Ontario Institute for Cancer Research; University of Toronto; Hospital for Sick Children (SickKids)
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2354
• DOI: 10.1038/s41586-025-08871-w
• 发表日期: 2025-06-12
• 关键词: acute myeloid-leukemia; clonal hematopoiesis; dnmt3a; RISK; metabolomics; carbon; tumors

摘要

Clonal haematopoiesis arises when a haematopoietic stem cell (HSC) acquires a mutation that confers a competitive advantage over wild-type HSCs, resulting in its clonal expansion. Individuals with clonal haematopoiesis are at increased risk of developing haematologic neoplasms and other age-related inflammatory illnesses1, 2, 3-4. Suppressing the expansion of mutant HSCs may prevent these outcomes; however, such interventions have not yet been identified. The most common clonal haematopoiesis driver mutations are in the DNMT3A gene, with arginine 882 (R882) being a mutation hotspot1, 2-3,5, 6-7. Here we show that mouse haematopoietic stem and progenitor cells (HSPCs) carrying the Dnmt3aR878H/+ mutation, equivalent to human DNMT3AR882H/+, have increased mitochondrial respiration compared with wild-type cells and are dependent on this metabolic reprogramming for their competitive advantage. Treatment with metformin, an anti-diabetic drug that inhibits mitochondrial respiration8, reduced the competitive advantage of Dnmt3aR878H/+ HSCs. Through a multi-omics approach, we found that metformin acts by enhancing methylation potential in Dnmt3aR878H/+ HSPCs and reversing the aberrant DNA CpG methylation and histone H3 K27 trimethylation profiles in these cells. Metformin also reduced the competitive advantage of human DNMT3AR882H HSPCs generated by prime editing. Our findings provide preclinical rationale for investigating metformin as a preventive intervention against DNMT3A R882 mutation-driven clonal haematopoiesis in humans.