Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis
Somatic DNMT3A-R882 codon mutations drive the most common form of clonal haematopoiesis (CH) and are associated with increased acute myeloid leukaemia (AML) risk<sup>1,2</sup>. Preventing expansion of DNMT3A-R882-mutant haematopoietic stem/progenitor cells (HSPCs) may therefore avert progression to AML. To identify DNMT3A-R882-mutant-specific vulnerabilities, we conducted a genome-wide CRISPR screen on primary mouse Dnmt3a<sup>R882H/+</sup> HSPCs. Among the 640 vulnerability genes identified, many were involved in mitochondrial metabolism, and metabolic flux analysis confirmed enhanced oxidative phosphorylation use in Dnmt3a<sup>R882H/+</sup> versus Dnmt3a<sup>+/+</sup> (WT) HSPCs. We selected citrate/malate transporter Slc25a1 and complex I component Ndufb11, for which pharmacological inhibitors are available, for downstream studies. In vivo administration of SLC25A1 inhibitor CTPI2 and complex I inhibitors IACS-010759 and metformin suppressed post-transplantation clonal expansion of Dnmt3a<sup>R882H/+</sup>, but not WT, long-term haematopoietic stem cells. The effect of metformin was recapitulated using a primary human DNMT3A-R882 CH sample. Notably, analysis of 412,234 UK Biobank participants showed that individuals taking metformin had a markedly lower prevalence of DNMT3A-R882-mutant CH, after controlling for potential confounders including glycated haemoglobin, diabetes and body mass index. Collectively, our data propose modulation of mitochondrial metabolism as a therapeutic strategy for prevention of DNMT3A-R882-mutant AML.
Authors
- Sarah J. Horton (ORCID: https://orcid.org/0000-0001-8418-5783)
- Kosuke Yusa (ORCID: https://orcid.org/0000-0002-3442-021X)
- Konstantinos Tzelepis (ORCID: https://orcid.org/0000-0002-4865-7648)
- Theodoros Georgomanolis (ORCID: https://orcid.org/0000-0002-4066-9257)
- Pedro M. Quirós (ORCID: https://orcid.org/0000-0002-7793-6291)
- Malgorzata Gozdecka
- Vijaya Baskar Mahalingam Shanmugiah
- Christian Frezza (ORCID: https://orcid.org/0000-0002-3293-7397)
- George Giotopoulos (ORCID: https://orcid.org/0000-0003-1390-6592)
- Paolo Gallipoli (ORCID: https://orcid.org/0000-0001-7254-2253)
- James A. Nathan (ORCID: https://orcid.org/0000-0002-0248-1632)
- George S. Vassiliou (ORCID: https://orcid.org/0000-0003-4337-8022)
- Ludovica Marando (ORCID: https://orcid.org/0000-0002-6154-850X)
- Guinevere L. Grice
- Rula Bany Bakar (ORCID: https://orcid.org/0000-0002-5643-0195)
- Brian J.P. Huntly (ORCID: https://orcid.org/0000-0003-0312-161X)
- Richard J Stopforth (ORCID: https://orcid.org/0000-0002-0054-7503)
- Aristi Damaskou
- Rachael Wilson (ORCID: https://orcid.org/0000-0001-5129-7295)
- Clea Bárcena (ORCID: https://orcid.org/0000-0002-7452-2536)
- Justyna Rak (ORCID: https://orcid.org/0000-0002-9398-4947)
- William G. Dunn (ORCID: https://orcid.org/0000-0001-7246-5198)
- Ryan Asby (ORCID: https://orcid.org/0000-0001-5077-3798)
- Penny Wright
- Arthur Kaser (ORCID: https://orcid.org/0000-0003-1419-3344)
- Margarete A. Fabre (ORCID: https://orcid.org/0000-0001-7794-610X)
- Eliza Yankova (ORCID: https://orcid.org/0000-0003-2913-0012)
- Muxin Gu (ORCID: https://orcid.org/0000-0003-4376-795X)
- Graham Duddy (ORCID: https://orcid.org/0009-0006-7834-7962)
- Annalisa Mupo (ORCID: https://orcid.org/0000-0002-2771-0462)
- Monika Dudek
- Siddhartha Kar (ORCID: https://orcid.org/0000-0002-2314-1426)
- Nisha Narayan (ORCID: https://orcid.org/0000-0002-4106-2166)
- Paul Carter (ORCID: https://orcid.org/0000-0002-9146-7540)
- Dean C. Pask
- Sean Wen
- Slavé Petrovski (ORCID: https://orcid.org/0000-0002-1527-961X)
- Laura Bond (ORCID: https://orcid.org/0000-0001-6115-655X)
- Jonathan Mitchell (ORCID: https://orcid.org/0000-0003-3792-4058)
- A. Ramesh (ORCID: https://orcid.org/0000-0003-4936-7754)
- Jonathan Cooper
- Matthew McLoughlin (ORCID: https://orcid.org/0000-0002-4782-5718)
Institutions
- Universidad de Oviedo (ES)
- Queen Mary University of London (GB)
- University of Cologne (DE)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Kyoto University (JP)
- University of Cambridge (GB)
- Royal Papworth Hospital (GB)
- The Francis Crick Institute (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Wellcome Sanger Institute (GB)
- Cancer Research UK Cambridge Center (GB)
- Canterbury Health Laboratories (NZ)
- AstraZeneca (Australia) (AU)
- Granta Design (United Kingdom) (GB)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- Addenbrooke's Hospital (GB)
- MRC Epidemiology Unit (GB)
Publication Details
- Journal
- Nature
- Published
- 2025-04-16
- DOI
- https://doi.org/10.1038/s41586-025-08980-6
- Citations
- 27
- Primary Topic
- Cancer Genomics and Diagnostics
- Type
- article
- Field-Weighted Citation Impact
- 25.28