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Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis

Author

Listed:
  • Malgorzata Gozdecka

    (University of Cambridge
    University of Cambridge)

  • Monika Dudek

    (University of Cambridge
    University of Cambridge)

  • Sean Wen

    (University of Cambridge
    AstraZeneca)

  • Muxin Gu

    (University of Cambridge
    University of Cambridge)

  • Richard J. Stopforth

    (University of Cambridge)

  • Justyna Rak

    (University of Cambridge
    University of Cambridge)

  • Aristi Damaskou

    (University of Cambridge
    University of Cambridge)

  • Guinevere L. Grice

    (University of Cambridge)

  • Matthew A. McLoughlin

    (University of Cambridge
    University of Cambridge)

  • Laura Bond

    (University of Cambridge
    University of Cambridge)

  • Rachael Wilson

    (University of Cambridge
    University of Cambridge)

  • George Giotopoulos

    (University of Cambridge
    University of Cambridge)

  • Vijaya Mahalingam Shanmugiah

    (University of Cambridge
    University of Cambridge)

  • Rula Bany Bakar

    (University of Cambridge)

  • Eliza Yankova

    (University of Cambridge
    University of Cambridge
    University of Cambridge)

  • Jonathan L. Cooper

    (University of Cambridge
    University of Cambridge)

  • Nisha Narayan

    (University of Cambridge
    University of Cambridge)

  • Sarah J. Horton

    (University of Cambridge
    University of Cambridge)

  • Ryan Asby

    (University of Cambridge
    University of Cambridge)

  • Dean C. Pask

    (University of Cambridge
    University of Cambridge)

  • Annalisa Mupo

    (Granta Park)

  • Graham Duddy

    (The Francis Crick Institute)

  • Ludovica Marando

    (University of Cambridge
    University of Cambridge)

  • Theodoros Georgomanolis

    (University Hospital Cologne)

  • Paul Carter

    (Cambridge Biomedical Campus)

  • Amirtha Priya Ramesh

    (University of Cambridge
    University of Cambridge)

  • William G. Dunn

    (University of Cambridge
    University of Cambridge)

  • Clea Barcena

    (University of Cambridge
    University of Cambridge
    Universidad de Oviedo)

  • 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
    University of Cambridge
    Universidad de Oviedo)

  • Christian Frezza

    (University Hospital Cologne
    University of Cologne)

  • James A. Nathan

    (University of Cambridge)

  • Arthur Kaser

    (University of Cambridge
    Addenbrooke’s Hospital)

  • Siddhartha Kar

    (University of Cambridge)

  • Konstantinos Tzelepis

    (University of Cambridge
    University of Cambridge
    University of Cambridge)

  • Jonathan Mitchell

    (AstraZeneca)

  • Margarete A. Fabre

    (University of Cambridge
    AstraZeneca
    Cambridge University Hospitals NHS Foundation Trust)

  • Brian J. P. Huntly

    (University of Cambridge
    University of Cambridge
    Cambridge University Hospitals NHS Foundation Trust)

  • George S. Vassiliou

    (University of Cambridge
    University of Cambridge
    Cambridge University Hospitals NHS Foundation Trust
    Hinxton)

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.

Suggested Citation

  • 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 Giot, 2025. "Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis," Nature, Nature, vol. 642(8067), pages 431-441, June.
    • Handle: RePEc:nat:nature:v:642:y:2025:i:8067:d:10.1038_s41586-025-08980-6
    DOI: 10.1038/s41586-025-08980-6
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