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Abstract Somatic DNMT3A -R882 codon mutations drive the most common form of clonal haematopoiesis (CH) and are associated with increased acute myeloid leukaemia (AML) risk 1,2 . 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 Dnmt3a R882H/+ HSPCs. Among the 640 vulnerability genes identified, many were involved in mitochondrial metabolism, and metabolic flux analysis confirmed enhanced oxidative phosphorylation use in Dnmt3a R882H/+ 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 R882H/+ , 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.
Gozdecka et al. (Wed,) studied this question.