Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis

• 成果类型: Article
• 署名作者: Gozdecka, Malgorzata; Dudek, Monika; Wen, Sean; Gu, Muxin; Stopforth, Richard J.; Rak, Justyna; Damaskou, Aristi; Grice, Guinevere L.; McLoughlin, Matthew A.; Bond, Laura; Wilson, Rachael; Giotopoulos, George; Shanmugiah, Vijaya Mahalingam; Bakar, Rula Bany; Yankova, Eliza; Cooper, Jonathan L.; Narayan, Nisha; Horton, Sarah J.; Asby, Ryan; Pask, Dean C.; Mupo, Annalisa; Duddy, Graham; Marando, Ludovica; Georgomanolis, Theodoros; Carter, Paul; Ramesh, Amirtha Priya; Dunn, William G.; Barcena, Clea; Gallipoli, Paolo; Yusa, Kosuke; Petrovski, Slave; Wright, Penny; Quiros, Pedro M.; Frezza, Christian; Nathan, James A.; Kaser, Arthur; Kar, Siddhartha; Tzelepis, Konstantinos; Mitchell, Jonathan; Fabre, Margarete A.; Huntly, Brian J. P.; Vassiliou, George S.
• 署名单位: University of Cambridge; University of Cambridge; AstraZeneca; University of Cambridge; University of Cambridge; Francis Crick Institute; University of Cologne; University of Cambridge; University of Oviedo; Instituto Universitario de Oncologia de Asturias; University of London; Queen Mary University London; Kyoto University; Canterbury Health Laboratories; University of Cologne; University of Cambridge; Cambridge University Hospitals NHS Foundation Trust; Addenbrooke's Hospital; University of Cambridge; University of Cambridge; Wellcome Trust Sanger Institute
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1345
• DOI: 10.1038/s41586-025-08980-6
• 发表日期: 2025-06-12
• 关键词: acute myeloid-leukemia; stem-cells; oxidative-phosphorylation; dnmt3a mutations; bethesda proposals; metformin; targets; cancer; AGE; CLASSIFICATION

摘要

Somatic DNMT3A-R882 codon mutations drive the most common form of clonal haematopoiesis (CH) and are associated with increased acute myeloid leukaemia (AML) risk1,2. 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 Dnmt3aR882H/+ HSPCs. Among the 640 vulnerability genes identified, many were involved in mitochondrial metabolism, and metabolic flux analysis confirmed enhanced oxidative phosphorylation use in Dnmt3aR882H/+ versus Dnmt3a+/+ (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 Dnmt3aR882H/+, 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.