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Pyruvate anaplerosis is a targetable vulnerability in persistent leukaemic stem cells

Author

Listed:
  • Kevin M. Rattigan

    (University of Glasgow)

  • Zuzana Brabcova

    (University of Glasgow)

  • Daniele Sarnello

    (University of Glasgow)

  • Martha M. Zarou

    (University of Glasgow)

  • Kiron Roy

    (University of Glasgow)

  • Ryan Kwan

    (Cancer Research UK Beatson Institute)

  • Lucie Beauchamp

    (University of Glasgow)

  • Amy Dawson

    (University of Glasgow)

  • Angela Ianniciello

    (University of Glasgow)

  • Ahmed Khalaf

    (University of Glasgow)

  • Eric R. Kalkman

    (University of Glasgow)

  • Mary T. Scott

    (University of Glasgow)

  • Karen Dunn

    (University of Glasgow)

  • David Sumpton

    (Cancer Research UK Beatson Institute)

  • Alison M. Michie

    (University of Glasgow)

  • Mhairi Copland

    (University of Glasgow)

  • Saverio Tardito

    (University of Glasgow
    Cancer Research UK Beatson Institute)

  • Eyal Gottlieb

    (Technion-Israel Institute of Technology)

  • G. Vignir Helgason

    (University of Glasgow)

Abstract

Deregulated oxidative metabolism is a hallmark of leukaemia. While tyrosine kinase inhibitors (TKIs) such as imatinib have increased survival of chronic myeloid leukaemia (CML) patients, they fail to eradicate disease-initiating leukemic stem cells (LSCs). Whether TKI-treated CML LSCs remain metabolically deregulated is unknown. Using clinically and physiologically relevant assays, we generate multi-omics datasets that offer unique insight into metabolic adaptation and nutrient fate in patient-derived CML LSCs. We demonstrate that LSCs have increased pyruvate anaplerosis, mediated by increased mitochondrial pyruvate carrier 1/2 (MPC1/2) levels and pyruvate carboxylase (PC) activity, in comparison to normal counterparts. While imatinib reverses BCR::ABL1-mediated LSC metabolic reprogramming, stable isotope-assisted metabolomics reveals that deregulated pyruvate anaplerosis is not affected by imatinib. Encouragingly, genetic ablation of pyruvate anaplerosis sensitises CML cells to imatinib. Finally, we demonstrate that MSDC-0160, a clinical orally-available MPC1/2 inhibitor, inhibits pyruvate anaplerosis and targets imatinib-resistant CML LSCs in robust pre-clinical CML models. Collectively these results highlight pyruvate anaplerosis as a persistent and therapeutically targetable vulnerability in imatinib-treated CML patient-derived samples.

Suggested Citation

  • Kevin M. Rattigan & Zuzana Brabcova & Daniele Sarnello & Martha M. Zarou & Kiron Roy & Ryan Kwan & Lucie Beauchamp & Amy Dawson & Angela Ianniciello & Ahmed Khalaf & Eric R. Kalkman & Mary T. Scott & , 2023. "Pyruvate anaplerosis is a targetable vulnerability in persistent leukaemic stem cells," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40222-z
    DOI: 10.1038/s41467-023-40222-z
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    References listed on IDEAS

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    1. Simon Raffel & Mattia Falcone & Niclas Kneisel & Jenny Hansson & Wei Wang & Christoph Lutz & Lars Bullinger & Gernot Poschet & Yannic Nonnenmacher & Andrea Barnert & Carsten Bahr & Petra Zeisberger & , 2017. "BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation," Nature, Nature, vol. 551(7680), pages 384-388, November.
    2. Sheela A. Abraham & Lisa E. M. Hopcroft & Emma Carrick & Mark E. Drotar & Karen Dunn & Andrew J. K. Williamson & Koorosh Korfi & Pablo Baquero & Laura E. Park & Mary T. Scott & Francesca Pellicano & A, 2016. "Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells," Nature, Nature, vol. 534(7607), pages 341-346, June.
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