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Survival and Proliferation of T-cell Acute Lymphoblastic Leukaemia Depends on mTOR-regulated Glutamine Uptake and EAAT1 Activity

ABSTRACT: With the aim to identify new therapeutic targets for T-ALL treatment, we integrated transcriptomics and metabolomics data, including live-cell NMR-spectroscopy, of cell lines and patient samples. We found that T-ALL cells have limited energy availability, resulting in down-regulated mTOR-signalling and reduced autophagy. Despite this, mTOR kinase activity is essential for the glutamine-uptake and rapid proliferation. T-ALL cells use glutamine as a source for all nitrogen atoms in purines and for all but one carbon in pyrimidines. We show that EAAT1, the glutamate-aspartate transporter normally only expressed in the CNS, is a crucial facilitator of the glutamine conversion to nucleotides. T-ALL cell proliferation depends on EAAT1 function, identifying it as a target for T-ALL treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE101566 | GEO | 2020/11/01

REPOSITORIES: GEO

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Homo sapiens

Project description:Survival and Proliferation of T-cell Acute Lymphoblastic Leukaemia Depends on mTOR-regulated Glutamine Uptake and EAAT1 Activity

| PRJNA394841 | ENA

Hyperglycemia and a Common Variant of GCKR Are Associated with the Levels of Eight Amino Acids in 9,371 Finnish Men

Project description:Objective: Insulin regulates amino acid metabolism. We investigated whether glycemia and 43 genetic risk variants for hyperglycemia/type 2 diabetes affect amino acid levels in a large population-based cohort. Subjects and Methods: A total of 9,371 non-diabetic or newly-diagnosed type 2 diabetic Finnish men from the population-based METSIM Study were studied. Proton NMR spectroscopy was used to measure plasma levels of 8 amino acids. Genotyping of 42 SNPs and mRNA microarray analysis from 200 subcutaneous adipose tissue samples were performed. Results: Increasing fasting and/or 2-hour plasma glucose levels were associated with increasing levels of alanine, valine, leucine, isoleucine, phenylalanine and tyrosine, and decreasing levels of histidine and glutamine. We also found significant correlations between insulin sensitivity (Matsuda ISI) and expression of genes regulating amino acid metabolism. Only one SNP (rs780094 in GCKR) of the 42 risk SNPs for type 2 diabetes or hyperglycemia was significantly associated with the levels of alanine, isoleucine, and glutamine. Conclusions : We observed that the levels of branched-chain, aromatic amino acids and alanine increased and the levels of glutamine and histidine decreased with increasing glycemia. These associations seemed to be mediated by insulin resistance, at least in part. GCKR rs780094 was significantly associated with several amino acids. Total RNA was obtained from subcutaneous fat biopsies from 200 people participating in the METSIM study (4 samples were replicated for a total of 204 arrays).

2012-04-01 | E-GEOD-32512 | biostudies-arrayexpress

Hyperglycemia and a Common Variant of GCKR Are Associated with the Levels of Eight Amino Acids in 9,371 Finnish Men

2012-04-02 | GSE32512 | GEO

Evaluating the transcriptomic and metabolic profile of mice exposed to source drinking water

Project description:Transcriptomic and metabonomic methods were used to investigate mice’s responses to drinking source water (DSW) exposure. After mice were fed with DSW for 90 days, hepatic transcriptome was characterized by microarray and serum metabonome were determined by 1H nuclear magnetic resonance (NMR) spectroscopy. A total of 243 differentially expressed genes (DEGs) were identified, among which 141 genes were up-regulated and 102 genes were down-regulated. Metabonomics revealed significant changes in concentrations of creatine, pyruvate, glutamine, lysine, choline, acetate, lipids, taurine and trimethylamine oxide. Four biological pathways were identified by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis where both gene expression and metabolite concentrations were altered in response to DSW exposure. These results highlight the significance of combined use of transcriptomic and metabonomic approaches in evaluating potential health risk induced by DSW contaminated with various hazardous materials.

2012-01-01 | GSE30940 | GEO

Brain tumor stem cell dependence on glutaminase reveals a metabolic vulnerability through the amino acid deprivation response pathway

Project description:Cancer cells can metabolize glutamine to replenish TCA cycle intermediates, leading to a dependence on glutaminolysis for cell survival. However, a mechanistic understanding of the role that glutamine metabolism has on the survival of glioblastoma (GBM) brain tumor stem cells (BTSCs) has not yet been elucidated. Here we report that, across a panel of twenty glioblastoma BTSC lines, glutaminase (GLS) inhibition showed a variable response – from complete blockade of cell growth to absolute resistance. Surprisingly, BTSC sensitivity to GLS inhibition was a result of reduced intracellular glutamate triggering the amino acid deprivation response (AADR) and not due to the contribution of glutaminolysis to the TCA cycle. Moreover, BTSC sensitivity to GLS inhibition negatively correlated with the expression of the astrocytic glutamate transporters EAAT1 and EAAT2. Blocking glutamate transport in BTSCs with high EAAT1/EAAT2 expression rendered these cells susceptible to GLS inhibition, triggering the AADR, and limiting cell growth. These findings uncover a unique metabolic vulnerability in BTSCs, support the therapeutic targeting of the upstream activators and downstream effectors of the AADR pathway in GBM, and demonstrate that gene expression patterns reflecting the cellular hierarchy of the tissue of origin can alter the metabolic requirements of the cancer stem cell population.

2020-12-25 | GSE155300 | GEO

Evaluating the transcriptomic and metabolic profile of mice exposed to source drinking water

2012-01-01 | E-GEOD-30940 | biostudies-arrayexpress

Change in miRNA levels in SH-SY5Y cells after electroporation of peptide nucleic acid (PNA) targeting precursor micro RNA

Project description:Peptide nucleic acid (PNA) is a neutral DNA analog uniquely suited for triple helical recognition of nucleic acids. However, the practical applications of triplex-forming PNAs have been limited by sequence restrictions, as stable base triples are formed only with purines. Hoogsteen recognition of pyrimidines has been a long-standing challenge. Here, a new approach to improve pyrimidine recognition by enhancing nucleobase stacking in the PNA strand is demonstrated by targeting procursor micro RNA (pre-miRNA). Placing 5-triazolyl uridine adjacent to the modified nucleobases designed for Hoogsteen recognition of pyrimidines in double helical RNA increased the binding affinity while maintaining sequence specificity. The increased binding affinity improved the biological activity of triplex-forming PNAs. RNA-seq analysis targeting mature microRNAs showed that a PNA recognizing a mixed sequence of three nucleobases (G, A, and U) had higher specificity than a similar PNA featuring a uniform purine recognition tract. These results demonstrate a novel strategy to address the issue of pyrimidine recognition, which has been the critical bottleneck for triple helical targeting of nucleic acids.

2026-03-05 | GSE307169 | GEO

BW25113 GhoS for RNase activity

Project description:To provide more evidence of the specificity of the RNase activity of GhoS, we performed a whole-transcriptome study for the production of GhoS vs. an empty plasmid so that we could investigate all of the cell’s transcripts for cleavage with GhoS, in vivo (i.e., BW25113/pCA24N-ghoS vs. BW25113/pCA24N with 1 mM IPTG induction of ghoS for 90 min). Under these conditions, only 20 genes were found to be repressed by more than 4-fold; there were no induced genes. These GhoS-repressed genes were all involved in the biosynthesis/transport of purines and pyrimidines; among them, pyrI was most highly repressed (-20 fold). These results suggest that GhoS selectively cleaves only a few cellular targets.

2012-08-30 | GSE36779 | GEO

Bulk RNA-seq of siGFPT2 and NC grouped H1975 cells

Project description:In the evolving field of cancer immunotherapy, EGFR-mutated NSCLC presents a significant challenge, demonstrating marked resistance to established treatments. An effective method to counter this resistance remains elusive. Through comprehensive genetic and pharmacological analyses across various models, we have identified glutamine fructose-6-phosphate transaminase 2 (GFPT2) as a key facilitator of immune evasion in EGFR-mutated NSCLC.

2024-06-10 | GSE269440 | GEO

Excitatory amino acid transporter 1 supports adult hippocampal neural stem cell self-renewal.

Project description:Within the adult mammalian dentate gyrus (DG) of the hippocampus, glutamate stimulates neural stem cell (NSC) self-renewing proliferation, providing a link between adult neurogenesis and local circuit activity. Here, we show that glutamate-induced self-renewal of adult DG NSCs requires glutamate transport via excitatory amino acid transporter 1 (EAAT1) to stimulate lipogenesis. Loss of EAAT1 prevented glutamate-induced self-renewing proliferation of NSCs in vitro and in vivo, with little role evident for canonical glutamate receptors. Transcriptomics and further pathway manipulation revealed that glutamate simulation of NSCs relied on EAAT1 transport-stimulated lipogenesis, likely secondary to intracellular Ca2+ release and glutamate metabolism. Our findings demonstrate a critical, direct role for EAAT1 in stimulating NSCs to support neurogenesis in adulthood, thereby providing insights into a non-canonical mechanism by which NSCs sense and respond their niche.

2023-06-14 | GSE217059 | GEO

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