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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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.
| 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. |
| Status: | Published |
| Refereed: | Yes |
| 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: | 2041-1723 |
| 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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