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. 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 HSPCs. Among the 640 vulnerability genes identified, many were involved in mitochondrial metabolism, and metabolic flux analysis confirmed enhanced oxidative phosphorylation use in Dnmt3a 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 Dnmt3a, 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.