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

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

PROVIDER: PRJNA941940 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23725022_1.fastq.gz	Fastqsanger.gz
	SRR23725022_2.fastq.gz	Fastqsanger.gz
	SRR23725023_1.fastq.gz	Fastqsanger.gz
	SRR23725023_2.fastq.gz	Fastqsanger.gz
	SRR23725024_1.fastq.gz	Fastqsanger.gz

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

Project description: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.

| S-EPMC10561355 | biostudies-literature

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

Project description:We tested the effect of arginine depleting enzyme BCT-100 (24 hours) on primary normal and CML cells (100ng/mL for primary) as well as the wildtype or ASS1 knock-out K562 cell lines (1000ng/mL for cell lines) Cells were cultured in Plasmax Primary groups were Normal, Normal+bct, CML, CML+BCT Cell line groups were WT, WT+bct, ASS1KO, ASS1KO+BCT

2023-07-25 | GSE226887 | GEO

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

Project description: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 Leukemia (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.

| S-SCDT-10_15252-EMBR_202256279 | biostudies-other

RSK1 is an exploitable dependency in myeloid malignancies [CD34RNAseq]