Arginine dependency is a therapeutically exploitable vulnerability in chronic myeloid leukaemic stem cells

Rattigan, K. M. et al. (2023) Arginine dependency is a therapeutically exploitable vulnerability in chronic myeloid leukaemic stem cells. EMBO Reports, 24, e56279. (doi: 10.15252/embr.202256279) (PMID:37489735) (PMCID:PMC10561355)

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To fuel accelerated proliferation, leukaemic cells undergo metabolic deregulation, which can result in specific nutrient dependencies. Here, we perform an amino acid drop-out screen and apply pre-clinical models of chronic phase chronic myeloid leukaemia (CML) to identify arginine as a nutrient essential for primary human CML cells. Analysis of the Microarray Innovations in Leukaemia (MILE) dataset uncovers reduced ASS1 levels in CML compared to most other leukaemia types. Stable isotope tracing reveals repressed activity of all urea cycle enzymes in patient-derived CML CD34+ cells, rendering them arginine auxotrophic. Thus, arginine deprivation completely blocks proliferation of CML CD34+ cells and induces significantly higher levels of apoptosis when compared to arginine-deprived cell lines. Similarly, primary CML cells, but not normal CD34+ samples, are particularly sensitive to treatment with the arginine-depleting enzyme, BCT-100, which induces apoptosis and reduces clonogenicity. Moreover, BCT-100 is highly efficacious in a patient-derived xenograft model, causing > 90% reduction in the number of human leukaemic stem cells (LSCs). These findings indicate arginine depletion to be a promising and novel strategy to eradicate therapy resistant LSCs.

Item Type:Articles
Additional Information:The authors thank the Core Services and Advanced Technologies at the Cancer Research UK Beatson Institute (C596/A17196; A31287). This work was supported by The Kay Kendall Leukaemia Fund (KKL1069), Blood Cancer UK (formerly Bloodwise; Ref 18006), Cancer Research UK (C57352/A29754), Cancer Research UK Glasgow Centre (A25142), The Howat Foundation, Tenovus Scotland and Friends of Paul O'Gorman Leukaemia Research Centre (all to GVH); NHS-GGC Endowment Fellowship (GN17ON425) to KMR; and Cancer Research UK to DS and ST (A23982).
Glasgow Author(s) Enlighten ID:Tardito, Dr Saverio and Dunn, Mrs Karen and Brabcova, Dr Zuzana and Zerbst, Désirée and Scott, Dr Mary and Ianniciello, Ms Angela and Sarnello, Daniele and Zarou, Martha-Maria and Sumpton, Mr David and Rattigan, Dr Kevin and Helgason, Professor Vignir and Copland, Professor Mhairi and Prasad, Dr Bodhayan and Kalkman, Dr Eric
Authors: Rattigan, K. M., Zarou, M. M., Brabcova, Z., Prasad, B., Zerbst, D., Sarnello, D., Kalkman, E. R., Ianniciello, A., Scott, M. T., Dunn, K., Shokry, E., Sumpton, D., Copland, M., Tardito, S., Vande Voorde, J., Mussai, F., Cheng, P., and Helgason, G. V.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:EMBO Reports
Publisher:EMBO Press
ISSN (Online):1469-3178
Published Online:25 July 2023
Copyright Holders:Copyright © 2023 The Authors
First Published:First published in EMBO Reports 24:e56279
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