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The S enantiomer of 2-hydroxyglutarate increases central memory CD8 populations and improves CAR-T therapy outcome

ABSTRACT: Study aim: Investigate the effect of S-2HG (2-hydroxyglutarate) metabolite on the mRNA levels of human CD8 T cells Methods: Naïve CD8 T cells were isolated from human healthy donors. The CD8 T cells were aCD3/CD28 beads (1:1 bead-to-cell ratio) and IL-2 (30 U/ml) for 4 days. The cells were treated with S-2HG (0.4 mM) or vehicle (H2O) from the day of isolation and for 12 days before collection. Library preparation and paired-end RNA sequencing using Illumina NextSeq 500, as well as downstream data analysis, were performed by Active Motif.

ORGANISM(S): Homo sapiens

PROVIDER: GSE155715 | GEO | 2020/08/05

REPOSITORIES: GEO

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The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function

Project description:2-hydroxyglutarate (2HG) is a by-product of the TCA cycle, and is readily detected in the tissues of healthy individuals. 2HG is found in two enantiomeric forms: S-2HG and R-2HG. Here, we investigate the differential roles of these two enantiomers in CD8+ T cell biology, where we found they had highly divergent effects on proliferation, differentiation, and T cell function. We show here an analysis of structural determinants that likely underlie these differential effects on specific a-ketoglutarate (aKG)-dependent enzymes. Treatment of CD8+ T cells with exogenous S-2HG, but not R-2HG, increased CD8+ T cell fitness in vivo, and enhanced anti-tumour activity. These data show that S-2HG and R-2HG should be considered as two distinct and important actors in the regulation of T cell function.

2023-07-21 | GSE212738 | GEO

2-hydroxyglutarate inhibits transcription factor mediated differentiation by preventing H3K9 demethylation

Project description:ATAC-seq associates impairment of myogenic differentiation in cells with an IDH2 mutation with differences in chromatin accessibility. Differences are especially apparent in regions flanking binding sites for myogenic regulatory factors and key myogenesis noncoding RNA linc-MD1. Oncogenic IDH1/2 mutations produce 2-hydroxyglutarate (2HG), resulting in competitive inhibition of DNA and protein demethylation. IDH-mutant cancer cells show an inability to differentiate but whether 2HG accumulation is sufficient to perturb differentiation directed by lineage-specifying transcription factors is unknown. A MyoD-driven model was used to study the role of IDH mutations in the differentiation of mesenchymal cells. The presence of 2HG produced by oncogenic IDH2 blocks the ability of MyoD to drive differentiation into myotubes. DNA 5mC hypermethylation is dispensable while H3K9 hypermethylation is required for this differentiation block. IDH2-R172K mutation results in H3K9 hypermethylation and impaired accessibility at myogenic chromatin regions but does not result in genome-wide decrease in accessibility. The results demonstrate the ability of the oncometabolite to 2HG block transcription factor-mediated differentiation in a molecularly defined system.

2019-06-10 | GSE118440 | GEO

D- 2-hydroxyglutarate is an immunometabolite that accumulates in macrophages after TLR activation and inhibits inflammatory responses

Project description:Macrophages undergo extensive metabolic rewiring upon activation and this serves many roles beyond the production of energy and anabolic building blocks. So-called immunometabolites that accumulate upon immune activation can serve as co-factors for enzymes and can mediate posttranslational modifications of histones, transcription factors, enzymes and other key proteins that modulate macrophage function. As such, the Krebs-cycle-associated metabolites succinate and itaconate emerged as key regulators of macrophages. 2-hydroxyglutarate (2HG) is structurally similar to Krebs-cycle metabolite alpha-ketoglutarate and exists as two enantiomers. D-2HG is well studied as an oncometabolite in cancer cells and more recently, L-2HG received some attention in the immunometabolism field. Here we describe that 2HG levels peak during later stages of LPS-induced inflammatory responses in mouse and human macrophages. Surprisingly, D-2HG was the most abundant enantiomer in macrophages and its LPS-induced accumulation may be explained by the inverse kinetics of D-2HG-degrading D-2HG dehydrogenase (D2HGDH) and the time-dependent induction of Hydroxyacid-Oxoacid Transhydrogenase (HOT), which makes D-2HG as a byproduct. D-2HG kinetics fit transcriptomics and functional data, together indicating that D-2HG suppresses inflammatory responses in macrophages in vitro. D-2HG also regulates local and systemic inflammatory responses in vivo. Finally, we show that D-2HG likely exerts in anti-inflammatory effects on NFkB target genes independently of aKG-dependent dioxygenases. Together, this study unexpectedly classifies D-2HG as an immunometabolite that can inhibit inflammatory macrophage responses.

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(R)-2-hydroxyglutarate inhibits KDM5 histone lysine demethylases to drive tumorigenesis in IDH-mutant cancers

Project description:Oncogenic mutations in isocitrate dehydrogenase (IDH)-1 and -2 occur in a wide range of cancers, including acute myeloid leukemias (AMLs) and gliomas1-3. Mutant IDH enzymes convert 2-oxoglutarate (2OG) to (R)-2-hydroxyglutarate [(R)-2HG]4,5, an oncometabolite that induces cellular transformation by dysregulating 2OG-dependent enzymes. The only direct target of (R)-2HG known to contribute to transformation is the 5-methylcytosine hydroxylase TET2, and there is ample evidence to suggest that (R)-2HG drives leukemogenesis at least in part by inhibiting TET26,7. However, IDH mutations, but not TET2 mutations, are specifically associated with aggressive hematologic diseases, suggesting that (R)-2HG has targets other than TET2 that contribute to mutant IDH-mediated transformation. Here, we report that (R)-2HG directly inhibits KDM5 histone lysine demethylases in IDH-mutant AMLs and gliomas to induce cellular transformation. These studies provide a functional link between dysregulation of histone lysine methylation and tumorigenesis in IDH-mutant cancers.

2023-03-01 | GSE184611 | GEO

The effect of the modulation of L2-hydroxyglutarate content in pachytene-diplotene cells of male mice

Project description:We found that testis of male mice contain high concentrations of L2-hydroxyglutarate (L2HG) specifically in germ cells at pachytene/ diplotene (PD) stage of spermatogenesis. In order to elucidate the function of 2HG we decreased its level by incubating PD cells with 24 mM oxamate and to rescue the putative phenotype by incubation with 24 mM oxamate together with 0.3 mM cell permeable L2HG.

2024-03-25 | GSE169015 | GEO

Sorted tumor RNA-seq of syngeneic murine mutant IDH1 ICC tumor model treated with IDH1 inhibitor against vehicle

Project description:IDH1 is the most commonly mutated metabolic gene across human cancers, with the highest mutational frequency observed in AML, glioma, chondrosarcoma, and intrahepatic cholangiocarcinoma. Mutations of the hot spot R132 codon alter the activity of the IDH1 enzyme, resulting in the NADPH-dependent conversion of alpha-ketoglutarate to (R)-2-hydroxyglutarate [(R)-2HG], which accumulates to mM levels within tumors. (R)-2HG competitively inhibits a range of enzymes that utilize alpha-ketoglutarate. Targets include the JmjC family histone demethylases and TET family DNA demethylases whose inhibition is linked to the altered epigenetic state characteristic of many mIDH tumors. To gain insight into the mechanisms underlying the anti-tumor efficacy of inhibition of mutant IDH1 we conducted RNA-sequencing (RNA-seq) analysis of purified tumor cells. For these studies, the immune-competent 2205 subcutaneous allograft model was treated with AG120 or vehicle for 6 days and non-tumor cells were removed by magnetic bead sorting (negative selection for CD45+ immune cells, CD31+ endothelial cells, TER119+ erythrocytes, and CD90.2+ fibroblasts).

2021-11-23 | E-MTAB-11112 | biostudies-arrayexpress

The effect of 2HG level on transcriptome at different stages of male mouse meiosis

Project description:We found that L2-hydroxyglutarate (2HG) level is 15 times higher in pachytene-diplotene (PD) stage as compared to leptotene-zygotene (LZ) stage. Since 2HG shows epigenetic effects we asked if the addition of 2HG to LZ cells or the decrease of 2HG level in PD cells will cause changes in gene expression.

2022-05-31 | GSE169014 | GEO

Gene expression profile of HCT116 and HT29 cells treated with D/L2HG

Project description:The oncometabolite, 2-hydroxyglutarate (2HG), has been directly implicated in carcinogenesis; however, the underlying molecular mechanisms remain poorly understood. To elucidate the molecular mechanisms through which 2HG contributes to cancer progression, we performed transcriptome analysis in 2HG-treated colorectal cancer HCT116 and HT29 cells.

2023-03-02 | GSE210167 | GEO

Isocitrate dehydrogenase 1 mutations prime the all-trans-retinoic acid myeloid differentiation pathway in acute myeloid leukemia HL-60 cells

Project description:Human acute myeloid leukemia HL60 cells were transduced with IDH1-WT or IDH1-R132H, and corresponding sub-clones were generated by FACS. In a first series of experiments, cells expressing wt and mutant IDH1were treated with either 1ÂµM all-trans retinoic acid (ATRA) or with vehicle (DMSO) for 24 hrs, resulting in 4 groups of samples (WT-CTRL, WT-ATRA, Mutant-CTRL, Mutant-ATRA). In a second series of assays, WT-IDH1 cells were pre-treated for 2 days with either 100 ÂµM octyl ester of (R)-2-hydroxyglutarate ((R)-2-HG) or 1-octanol (octyl), and then treated with 1 ÂµM ATRA or vehicle for 24 hrs, again resulting in 4 groups of samples (Octyl-CTRL, Octyl-ATRA, 2HG-CTRL, 2HG-ATRA). All assays were performed in triplicate (4 replicates for Mutant-CTRL and Mutant-ATRA).

2017-03-01 | E-MTAB-4327 | biostudies-arrayexpress

genomic profiling of mouse CD8 T cells electroporated with non-targeting or AR-specific gRNAs

Project description:Purpose: Determine the change in expression of genes in AR deficient CD8 T cells Methods: C57Bl/6J splenocytes were isolated, total CD8 T cells magnetically enriched and electroporated with non-targeting gRNA or AR-specific gRNAs. Cells were stimulated with aCD3/28 for three days before isolating RNA and library prep. Sequencing was performed by the Massively Parallel Sequencing Shared Resource (MPSSR) at OHSU. Results: AR regulated genes in mouse CD8 T cells.

2023-03-01 | GSE198874 | GEO

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