Pyruvate anaplerosis is a targetable vulnerability in persistent leukaemic stem cells

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, Karen Dunn, David Sumpton, Alison M. Michie, Mhairi Copland, Saverio Tardito, Eyal Gottlieb and G. Vignir Helgason ()
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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
Eyal Gottlieb: Technion-Israel Institute of Technology
G. Vignir Helgason: University of Glasgow

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40222-z

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