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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 Slavé, 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
Аннотация
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.