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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells Expression data for Xenograft Samples

ABSTRACT: The recent discovery of mutations in metabolic enzymes has rekindled interest in harnessing the altered metabolism of cancer cells for cancer therapy. One potential drug target is isocitrate dehydrogenase 1 (IDH1) which is mutated in multiple human cancers. Here, we examine the role of mutant IDH1 in fully transformed cells with endogenous IDH1 mutations. A selective R132H-IDH1 inhibitor (AGI-5198) identified through a high-throughput screen dose-dependently blocked the ability of the mutant enzyme (mIDH1) to produce R-2-hydroxyglutarate (R-2HG). Under conditions of near complete R-2HG inhibition, the mIDH1 inhibitor induced demethylation of histone H3K9M3 and expression of genes associated with gliogenic differentiation. Blockade of mIDH1 impaired the growth of IDH1-mutant - but not IDH1-wildtype – glioma cells without appreciable changes in genome wide DNA methylation. These data suggest that mIDH1 may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects. Two xenograft experiments were carried out, one with treatment cohorts of vehicle and 450mg/kg, and the other with vehicle, 150mg/kg/day, and 450mg/kg/day. After the indicated time tumors were harvested and total RNA was extracted and analyzed by the Affymetrix U133 plus 2 array.

ORGANISM(S): Homo sapiens

SUBMITTER: Daniel Rohle

PROVIDER: E-GEOD-45197 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells Methylation Data for Xenograft Samples

Project description:The recent discovery of mutations in metabolic enzymes has rekindled interest in harnessing the altered metabolism of cancer cells for cancer therapy. One potential drug target is isocitrate dehydrogenase 1 (IDH1) which is mutated in multiple human cancers. Here, we examine the role of mutant IDH1 in fully transformed cells with endogenous IDH1 mutations. A selective R132H-IDH1 inhibitor (AGI-5198) identified through a high-throughput screen dose-dependently blocked the ability of the mutant enzyme (mIDH1) to produce R-2-hydroxyglutarate (R-2HG). Under conditions of near complete R-2HG inhibition, the mIDH1 inhibitor induced demethylation of histone H3K9M3 and expression of genes associated with gliogenic differentiation. Blockade of mIDH1 impaired the growth of IDH1-mutant - but not IDH1-wildtype – glioma cells without appreciable changes in genome wide DNA methylation. These data suggest that mIDH1 may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects. Xenograft experiments were carried out with treatment cohorts of vehicle, 150mg/kg/day, 450mg/kg/day. After the indicated tumors were harvested and genomic DNA was extracted and analyzed by the Illumina 450k Methylation array.

2013-04-04 | E-GEOD-45198 | biostudies-arrayexpress

An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells Methylation Data for In Vitro Model

2013-04-04 | GSE45199 | GEO

An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells Methylation Data for Xenograft Samples

2013-04-04 | GSE45198 | GEO

An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells Expression data for Xenograft Samples

2013-04-04 | GSE45197 | GEO

An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells Methylation Data for In Vitro Model

Project description:The recent discovery of mutations in metabolic enzymes has rekindled interest in harnessing the altered metabolism of cancer cells for cancer therapy. One potential drug target is isocitrate dehydrogenase 1 (IDH1) which is mutated in multiple human cancers. Here, we examine the role of mutant IDH1 in fully transformed cells with endogenous IDH1 mutations. A selective R132H-IDH1 inhibitor (AGI-5198) identified through a high-throughput screen dose-dependently blocked the ability of the mutant enzyme (mIDH1) to produce R-2-hydroxyglutarate (R-2HG). Under conditions of near complete R-2HG inhibition, the mIDH1 inhibitor induced demethylation of histone H3K9M3 and expression of genes associated with gliogenic differentiation. Blockade of mIDH1 impaired the growth of IDH1-mutant - but not IDH1-wildtype – glioma cells without appreciable changes in genome wide DNA methylation. These data suggest that mIDH1 may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects. Samples were maintained in either DMSO or 1.5uM 5198 for 2 passages up to 20 passages. Biological replicates for each passage and treatment was collected and genomic DNA was extracted and analyzed on the Illumina 450K Methylation platform for a total of 16 samples.

2013-04-04 | E-GEOD-45199 | biostudies-arrayexpress

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

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

Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1

Project description:IDH1 mutation is the earliest genetic alteration in low-grade gliomas (LGGs), but its role in tumor recurrence is unclear. Mutant IDH1 drives overproduction of the oncometabolite D-2-hydroxyglutarate (2HG) and a CpG island (CGI) hypermethylation phenotype (G-CIMP). To investigate the role of mutant IDH1 at recurrence, we performed a longitudinal analysis of 50 IDH1 mutant LGGs. We discovered six cases with copy number alterations (CNAs) at the IDH1 locus at recurrence. Deletion or amplification of IDH1 was followed by clonal expansion and recurrence at a higher grade. Successful cultures derived from IDH1 mutant, but not IDH1 wild-type, gliomas systematically deleted IDH1 in vitro and in vivo, further suggestive of selection against the heterozygous mutant state as tumors progress. Tumors and cultures with IDH1 CNA had decreased 2HG, maintenance of G-CIMP, and DNA methylation reprogramming outside CGI. Thus, while IDH1 mutation initiates gliomagenesis, in some patients, mutant IDH1 and 2HG are not required for later clonal expansions.

| EGAS00001001854 | EGA

Gene expression changes induced by overexpression of IDH1mut and treatment with 2HG in the sorted mouse bone marrow cells

Project description:Mutations in the enzymes IDH1 and IDH2 have been identified in a wide variety of tumors like glioma, chondrosarcoma, thyroid cancer, lymphoma, melanoma, and in acute myeloid leukemia. Mutated IDH1/2 produces the metabolite 2-hydroxyglutarate (2HG), which interferes with epigenetic regulation of gene expression, and thus may promote tumorigenesis.

2016-06-01 | GSE77594 | GEO

Gene expression changes induced by overexpression of IDH1mut in the sorted mouse bone marrow cells

2013-11-05 | GSE45019 | GEO

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