Pyruvate anaplerosis is a targetable vulnerability in persistent leukaemic stem cells (original) (raw)
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)
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 |
University Staff: Request a correction | Enlighten Editors: Update this record
Funder and Project Information
Identifying and Targeting Metabolic Dependencies in Tyrosine Kinase-Driven Myeloid Leukaemias
Vignir Helgason
KKL1069
SCS - Paul O'Gorman Leukaemia Research Centre
Targeting mitochondrial fuel oxidation for the treatment of chronic and acute myeloid leukaemias
Vignir Helgason
18006
SCS - Paul O'Gorman Leukaemia Research Centre
Targeting Autophagy and Aberrant Metabolism of Leukaemic Stem Cells
Vignir Helgason
C57352/A29754
SCS - Therapeutic Science Research
CRUK Centre Renewal
Owen Sansom
C7932/A25142
SCS - Beatson Institute for Cancer Research
Complementing LCMS data with transcriptomics to target metabolic vulnerabilities in acute myeloid leukaemia
Vignir Helgason
GN17ON425
SCS - Paul O'Gorman Leukaemia Research Centre
Deposit and Record Details
| ID Code: | 303307 |
|---|---|
| Depositing User: | Mr Matt Mahon |
| Datestamp: | 31 Aug 2023 09:50 |
| Last Modified: | 16 Jan 2024 11:10 |
| Date of acceptance: | 18 July 2023 |
| Date of first online publication: | 17 August 2023 |
| Date Deposited: | 20 July 2023 |
| Data Availability Statement: | Yes |