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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Abstract
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). |
| Status: | Published |
| Refereed: | Yes |
| 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: | 1469-221X |
| 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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