Modulation of mitochondrial metabolism curtails expansion of DNMT3A-R882 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 Dnmt3aR882H/+ HSPCs. Amongst the 640 identified vulnerability genes, many were involved in mitochondrial metabolism and metabolic flux analysis confirmed enhanced oxidative phosphorylation (OXPHOS) usage in Dnmt3aR882H/+ vs Dnmt3a+/+ (WT) HSPCs. Thus, 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 LT-HSCs. Notably, analysis of 412,234 UK Biobank participants revealed that individuals taking metformin exhibited a markedly lower prevalence of DNMT3A-R882-mutant CH (OR = 0.49, P = 0.00081). Our data propose that modulation of mitochondrial metabolism warrants urgent investigation as a therapeutic strategy for prevention of DNMT3A-R882-mutant AML.