Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis

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.

Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis

Malgorzata Gozdecka (), Monika Dudek, Sean Wen, Muxin Gu, Richard J. Stopforth, Justyna Rak, Aristi Damaskou, Guinevere L. Grice, Matthew A. McLoughlin, Laura Bond, Rachael Wilson, George Giotopoulos, Vijaya Mahalingam Shanmugiah, Rula Bany Bakar, Eliza Yankova, Jonathan L. Cooper, Nisha Narayan, Sarah J. Horton, Ryan Asby, Dean C. Pask, Annalisa Mupo, Graham Duddy, Ludovica Marando, Theodoros Georgomanolis, Paul Carter, Amirtha Priya Ramesh, William G. Dunn, Clea Barcena, Paolo Gallipoli, Kosuke Yusa, Slavé Petrovski, Penny Wright, Pedro M. Quiros, Christian Frezza, James A. Nathan, Arthur Kaser, Siddhartha Kar, Konstantinos Tzelepis, Jonathan Mitchell, Margarete A. Fabre, Brian J. P. Huntly () and George S. Vassiliou ()
Additional contact information
Malgorzata Gozdecka: University of Cambridge
Monika Dudek: University of Cambridge
Sean Wen: University of Cambridge
Muxin Gu: University of Cambridge
Richard J. Stopforth: University of Cambridge
Justyna Rak: University of Cambridge
Aristi Damaskou: University of Cambridge
Guinevere L. Grice: University of Cambridge
Matthew A. McLoughlin: University of Cambridge
Laura Bond: University of Cambridge
Rachael Wilson: University of Cambridge
George Giotopoulos: University of Cambridge
Vijaya Mahalingam Shanmugiah: University of Cambridge
Rula Bany Bakar: University of Cambridge
Eliza Yankova: University of Cambridge
Jonathan L. Cooper: University of Cambridge
Nisha Narayan: University of Cambridge
Sarah J. Horton: University of Cambridge
Ryan Asby: University of Cambridge
Dean C. Pask: University of Cambridge
Annalisa Mupo: Granta Park
Graham Duddy: The Francis Crick Institute
Ludovica Marando: University of Cambridge
Theodoros Georgomanolis: University Hospital Cologne
Paul Carter: Cambridge Biomedical Campus
Amirtha Priya Ramesh: University of Cambridge
William G. Dunn: University of Cambridge
Clea Barcena: University of Cambridge
Paolo Gallipoli: Queen Mary University of London
Kosuke Yusa: Kyoto University
Slavé Petrovski: AstraZeneca
Penny Wright: Canterbury Health Laboratories
Pedro M. Quiros: University of Cambridge
Christian Frezza: University Hospital Cologne
James A. Nathan: University of Cambridge
Arthur Kaser: University of Cambridge
Siddhartha Kar: University of Cambridge
Konstantinos Tzelepis: University of Cambridge
Jonathan Mitchell: AstraZeneca
Margarete A. Fabre: University of Cambridge
Brian J. P. Huntly: University of Cambridge
George S. Vassiliou: University of Cambridge

Nature, 2025, vol. 642, issue 8067, 431-441

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41586-025-08980-6

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