Metformin reduces the competitive advantage of Dnmt3aR878H HSPCs

Mohsen Hosseini, Veronique Voisin, Ali Chegini, Angelica Varesi, Severine Cathelin, Dhanoop Manikoth Ayyathan, Alex C. H. Liu, Yitong Yang, Vivian Wang, Abdula Maher, Eric Grignano, Julie A. Reisz, Angelo D’Alessandro, Kira Young, Yiyan Wu, Martina Fiumara, Samuele Ferrari, Luigi Naldini, Federico Gaiti, Shraddha Pai, Grace Egan, Aaron D. Schimmer, Gary D. Bader, John E. Dick, Stephanie Z. Xie, Jennifer J. Trowbridge and Steven M. Chan ()
Additional contact information
Mohsen Hosseini: Princess Margaret Cancer Centre
Veronique Voisin: Donnelly Centre for Cellular and Biomolecular Research
Ali Chegini: Princess Margaret Cancer Centre
Angelica Varesi: Princess Margaret Cancer Centre
Severine Cathelin: Princess Margaret Cancer Centre
Dhanoop Manikoth Ayyathan: Princess Margaret Cancer Centre
Alex C. H. Liu: Princess Margaret Cancer Centre
Yitong Yang: Princess Margaret Cancer Centre
Vivian Wang: Princess Margaret Cancer Centre
Abdula Maher: Princess Margaret Cancer Centre
Eric Grignano: Princess Margaret Cancer Centre
Julie A. Reisz: University of Colorado Anschutz Medical Campus
Angelo D’Alessandro: University of Colorado Anschutz Medical Campus
Kira Young: The Jackson Laboratory
Yiyan Wu: University of Toronto
Martina Fiumara: IRCCS San Raffaele Scientific Institute
Samuele Ferrari: IRCCS San Raffaele Scientific Institute
Luigi Naldini: IRCCS San Raffaele Scientific Institute
Federico Gaiti: Princess Margaret Cancer Centre
Shraddha Pai: Donnelly Centre for Cellular and Biomolecular Research
Grace Egan: Princess Margaret Cancer Centre
Aaron D. Schimmer: Princess Margaret Cancer Centre
Gary D. Bader: Donnelly Centre for Cellular and Biomolecular Research
John E. Dick: Princess Margaret Cancer Centre
Stephanie Z. Xie: Princess Margaret Cancer Centre
Jennifer J. Trowbridge: The Jackson Laboratory
Steven M. Chan: Princess Margaret Cancer Centre

Nature, 2025, vol. 642, issue 8067, 421-430

Abstract: Abstract 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 illnesses1–4. 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 hotspot1–3,5–7. 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.

Date: 2025
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DOI: 10.1038/s41586-025-08871-w

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