Pyruvate anaplerosis is a targetable vulnerability in persistent leukaemic stem cells

Rattigan, K. M. et al. (2023) Pyruvate anaplerosis is a targetable vulnerability in persistent leukaemic stem cells. Nature Communications, 14, 4634. (doi: 10.1038/s41467-023-40222-z) (PMID:37591854) (PMCID:PMC10435520)

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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.

Item Type:Articles
Additional Information:This work was funded by The Kay Kendall Leukemia Fund (KKL1069), Blood Cancer UK (formerly Bloodwise; Ref 18006), The Howat Foundation, Cancer Research UK (C57352/A29754), Tenovus Scotland, Cancer Research UK Glasgow Centre (A25142), Friends of Paul O’Gorman Leukaemia Research Centre (all to G.V.H.); NHSGGC Endowment Fellowship (GN17ON425) to K.M.R.; Cancer Research UK Glasgow (A23982) to S.T. and Cancer Research UK Glasgow core funding (A31287) to D.S.2, S.T. and the Cancer Research UK Beatson Institute.
Glasgow Author(s) Enlighten ID:Tardito, Dr Saverio and Brabcova, Dr Zuzana and Scott, Dr Mary and Ianniciello, Ms Angela and Gottlieb, Professor Eyal and Zarou, Martha-Maria and Sumpton, Mr David and Rattigan, Dr Kevin and Robert de Beauchamp, Lucie and Roy, Mr Kiron and Michie, Professor Alison and Khalaf, Mr Ahmed and Helgason, Professor Vignir and Kalkman, Dr Eric and Dawson, Ms Amy and Dunn, Mrs Karen and Sarnello, Daniele and Copland, Professor Mhairi
Authors: Rattigan, K. M., Brabcova, Z., Sarnello, D., Zarou, M. M., Roy, K., Kwan, R., de Beauchamp, L., Dawson, A., Ianniciello, A., Khalaf, A., Kalkman, E. R., Scott, M. T., Dunn, K., Sumpton, D., Michie, A. M., Copland, M., Tardito, S., Gottlieb, E., and Helgason, G. V.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Nature Communications
Publisher:Nature Research
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2023 The Authors
First Published:First published in Nature Communications 14:4634
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
173136Identifying and Targeting Metabolic Dependencies in Tyrosine Kinase-Driven Myeloid LeukaemiasVignir HelgasonThe Kay Kendall Leukaemia Fund (KENDALL)KKL1069SCS - Paul O'Gorman Leukaemia Research Centre
303409Targeting mitochondrial fuel oxidation for the treatment of chronic and acute myeloid leukaemiasVignir HelgasonBloodwise (BLOODWIS)18006SCS - Paul O'Gorman Leukaemia Research Centre
307077Targeting Autophagy and Aberrant Metabolism of Leukaemic Stem CellsVignir HelgasonCancer Research UK (CRUK)C57352/A29754SCS - Therapeutic Science Research
174115CRUK Centre RenewalOwen SansomCancer Research UK (CRUK)C7932/A25142SCS - Beatson Institute for Cancer Research
301323Complementing LCMS data with transcriptomics to target metabolic vulnerabilities in acute myeloid leukaemiaVignir HelgasonNHS Greater Glasgow and Clyde Endowment Funds (NHSGGCEN)GN17ON425SCS - Paul O'Gorman Leukaemia Research Centre