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

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 esse...

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Bibliographic Details
Published in:EMBO reports 2023-10, Vol.24 (10), p.e56279-e56279
Main Authors: Rattigan, Kevin M, Zarou, Martha M, Brabcova, Zuzana, Prasad, Bodhayan, Zerbst, Désirée, Sarnello, Daniele, Kalkman, Eric R, Ianniciello, Angela, Scott, Mary T, Dunn, Karen, Shokry, Engy, Sumpton, David, Copland, Mhairi, Tardito, Saverio, Vande Voorde, Johan, Mussai, Francis, Cheng, Paul, Helgason, G Vignir
Format: Article
Language:English
Subjects:
Amino acids
Apoptosis
Arginine
CD34 antigen
Cell lines
Cell proliferation
Chronic myeloid leukemia
Citrulline
Depletion
Deprivation
Deregulation
Drug resistance
Enzymes
Leukemia
Nutrients
Patients
Stable isotopes
Stem cells
Transcriptomes
Transcriptomics
Urea
Xenografts
Xenotransplantation
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Summary: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.
ISSN:1469-221X
1469-3178
DOI:10.15252/embr.202256279