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

ABSTRACT: 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE226887 | GEO | 2023/07/25

REPOSITORIES: GEO

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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: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

Pyruvate Anaplerosis is a Targetable Vulnerability in Persistent Leukaemic Stem Cells

Project description:Deregulated oxidative metabolism is a hallmark of leukaemia. While use of tyrosine kinase inhibitors (TKIs) such as imatinib has led to increased survival of chronic myeloid leukaemia (CML) patients, it fails 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 generated multi-omics datasets that offer unprecedented insight into nutrient fate in patient derived CML LSCs. We demonstrate that LSCs have increased glucose anaplerosis when compared to normal hematopoietic stem cells. While imatinib treatment reverses BCR-ABL-mediated LSC metabolic reprogramming, stable isotope-assisted metabolomics revealed that deregulated glucose anaplerosis is unaffected by imatinib. Encouragingly, genetic ablation of glucose anaplerosis sensitises CML cells to imatinib. Finally, we demonstrate that the clinical oral-available inhibitor MSDC-0160 targets glucose anaplerosis in robust pre-clinical CML models. Collectively these results highlight glucose anaplerosis as a persistent and therapeutically targetable vulnerability in imatinib-treated CML patient samples.

2023-06-27 | GSE216837 | GEO

CML proteome analysis, QSTAR - Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells

Project description:Using mass spectrometry the proteomesof CML were compared to normal tissue.

2016-06-03 | PXD001503 | Pride

Global transcriptomics of murine splenic B cells after treatment with BAFF 3mer and 60mer in presence of a control antibody or mBaffR-mFc

Project description:Mouse splenic total B cells (6 million cells/sample) were pre-treated with the control Ab (1000ng/ml, IgG1κ, BioXCell, #BE0083) or mBaffR-mFc (1000ng/ml, a fusion protein consists of murine BR3 ecto-domain fused to murine IgG1 Fc fragment obtained from Biogen, US) for 30 min, and then treated with 100 ng/ml of recombinant human BAFF 3mer (AdipoGen, #AG-40B-0016), 60mer (AdipoGen, #AG-40B-0112) or left untreated for the next 4 hours. Each treatment was in triplicates. Total RNA was extracted from the samples using QIAGEN RNeasy Mini Kit and were sent to Novogene Corporation (Wilmingtom, DE, USA) to determine the gene expression levels.

2023-11-08 | GSE161072 | GEO

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

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

| PRJNA941940 | ENA

TMEM30A loss-of-function mutations drive lymphomagenesis and confer therapeutically exploitable vulnerability in B-cell lymphoma.

Project description:Transmembrane protein 30A (TMEM30A) maintains the asymmetric distribution of phosphatidylserine, an integral component of the cell membrane and 'eat-me' signal recognized by macrophages. Integrative genomic and transcriptomic analysis of diffuse large B-cell lymphoma (DLBCL) from the British Columbia population-based registry uncovered recurrent biallelic TMEM30A loss-of-function mutations, which were associated with a favorable outcome and uniquely observed in DLBCL. Using TMEM30A-knockout systems, increased accumulation of chemotherapy drugs was observed in TMEM30A-knockout cell lines and TMEM30A-mutated primary cells, explaining the improved treatment outcome. Furthermore, we found increased tumor-associated macrophages and an enhanced effect of anti-CD47 blockade limiting tumor growth in TMEM30A-knockout models. By contrast, we show that TMEM30A loss-of-function increases B-cell signaling following antigen stimulation-a mechanism conferring selective advantage during B-cell lymphoma development. Our data highlight a multifaceted role for TMEM30A in B-cell lymphomagenesis, and characterize intrinsic and extrinsic vulnerabilities of cancer cells that can be therapeutically exploited.

| S-EPMC8480332 | biostudies-literature

Chronic Myeloid Leukemia (CML), induced pluripotent stem cell (iPSC)-derived lin-CD34+CD45+ (iCD34) cell population

2014-08-31 | GSE60065 | GEO

Downregulation of DNA repair proteins and increased DNA damage in hypoxic colon cancer cells is a therapeutically exploitable vulnerability.

Project description:Surgical removal of colorectal cancer (CRC) liver metastases generates areas of tissue hypoxia. Hypoxia imposes a stem-like phenotype on residual tumor cells and promotes tumor recurrence. Moreover, in primary CRC, gene expression signatures reflecting hypoxia and a stem-like phenotype are highly expressed in the aggressive Consensus Molecular Subtype 4 (CMS4). Therapeutic strategies eliminating hypoxic stem-like cells may limit recurrence following resection of primary tumors or metastases. Here we show that expression of DNA repair genes is strongly suppressed in CMS4 and inversely correlated with hypoxia-inducible factor-1 alpha (HIF1α) and HIF-2α co-expression signatures. Tumors with high expression of HIF signatures and low expression of repair proteins showed the worst survival. In human tumors, expression of the repair proteins RAD51, KU70 and RIF1 was strongly suppressed in hypoxic peri-necrotic tumor areas. Experimentally induced hypoxia in patient derived colonospheres in vitro or in vivo (through vascular clamping) was sufficient to downregulate repair protein expression and caused DNA damage. Hypoxia-induced DNA damage was prevented by expressing the hydroperoxide-scavenging enzyme glutathione peroxidase-2 (GPx2), indicating that reactive oxygen species mediate hypoxia-induced DNA damage. Finally, the hypoxia-activated prodrug Tirapazamine greatly augmented DNA damage and reduced the fraction of stem-like (Aldefluorbright) tumor cells in vitro, and in vivo following vascular clamping. We conclude that decreased expression of DNA repair proteins and increased DNA damage in hypoxic tumor areas may be therapeutically exploited with hypoxia-activated prodrugs, and that such drugs reduce the fraction of Aldefluorbright (stem-like) tumor cells.

| S-EPMC5689686 | biostudies-literature

Chronic Myeloid Leukemia (CML), induced pluripotent stem cell (iPSC)-derived lin-CD34+CD45+ (iCD34) cell population

Project description:Analysis of lin-CD34+CD45+ (iCD34+) cell population from two normal bone marrow-derived (BM1K and BM9) iPSCs and two CML (CML15 and CML17) iPSCs . CML iCD34+ cells have characteristics similar to primary CML leukemia stem cell in patients. Results provide insight into molecular profile characterized CML iCD34 and mechanism of its maintenance and drug resistance. iCD34+ cell samples obtained from two control BM1K and BM9 iPSCs (both for the same normal donor) and CML15 and CML17 iPSCs (both from the same patient in chronic phase of CML). Each group was treated with DMSO (control) or 5 μM imatinib. The complete phenotype for iCD34+ cells: lin-CD34+CD45+CD90+CD117+CD45RA-. This population also inclyde Rhodaminelow and ALDKhigh cells.

2014-08-31 | E-GEOD-60065 | biostudies-arrayexpress

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