Metformin reduces the competitive advantage of Dnmt3a
Document Type
Article
Publication Date
6-1-2025
Original Citation
Hosseini M,
Voisin V,
Chegini A,
Varesi A,
Cathelin S,
Ayyathan D,
Liu A,
Yang Y,
Wang V,
Maher A,
Grignano E,
Reisz J,
D'Alessandro A,
Young K,
Wu Y,
Fiumara M,
Ferrari S,
Naldini L,
Gaiti F,
Pai S,
Egan G,
Schimmer A,
Bader G,
Dick J,
Xie S,
Trowbridge JJ,
Chan S.
Metformin reduces the competitive advantage of Dnmt3a Nature. 2025;642(8067):421-30. Epub 20250416.
Keywords
Animals, Hematopoietic Stem Cells, DNA Methyltransferase 3A, Mice, DNA (Cytosine-5-)-Methyltransferases, Metformin, Mitochondria, DNA Methylation, Humans, Histones, Male, Female, Mutation, Cell Competition, Cell Respiration, Clonal Hematopoiesis, Clone Cells
JAX Source
Nature. 2025;642(8067):421-30. Epub 20250416.
ISSN
1476-4687
PMID
40240595
DOI
https://doi.org/10.1038/s41586-025-08871-w
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 illnesses 1–4 . 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 hotspot 1–3,5–7 . 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 respiration 8 , 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.