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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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE45197 | GEO | 2013/04/04

SECONDARY ACCESSION(S): PRJNA193199

REPOSITORIES: GEO

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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

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

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. 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.

2013-04-04 | E-GEOD-45197 | biostudies-arrayexpress

Zinc Finger MYND-Type Containing 8 (ZMYND8) is epigenetically regulated in mutant Isocitrate Dehydrogenase 1 (IDH1) glioma to promote radioresistance [ChIP-seq]

Project description:Mutant isocitrate dehydrogenase 1 (mIDH1) alters the epigenetic regulation of chromatin, leading to a hypermethylation phenotype in adult glioma. This work focuses on identifying gene targets epigenetically dysregulated by mIDH1 to confer therapeutic resistance to ionizing radiation (IR). We evaluated changes in the transcriptome and epigenome in a radioresistant mIDH1 patient-derived glioma cell culture (GCC) following treatment with an mIDH1 specific inhibitor AGI-5198. We identified Zinc Finger MYND-Type Containing 8 (ZMYND8) as potential target of mIDH1 reprogramming. We suppressed ZMYND8 expression by shRNA knockdown and genetic knockout (KO) in mIDH1 glioma cells then assessed cellular viability to IR. We assessed the sensitivity of mIDH1 GCCS to pharmacological inhibition of ZMYND8-interacting partners: HDAC, BRD4, and PARP. Inhibition of mIDH1 lead to an upregulation of gene networks involved in replication stress. We found that the expression of ZMYND8, a regulator of DNA damage response was decreased in three patient-derived mIDH1 GCCs after treatment with AGI-5198. Knockdown of ZMYND8 expression sensitized mIDH1 GCCs to radiotherapy marked by decreased cellular viability. Following IR, mIDH1 glioma cells with ZMYND8 knockout (KO) exhibit significant phosphorylation of ATM and sustained γH2AX activation. ZMYND8 KO mIDH1 GCCs were further responsive to IR when treated with either BRD4 or HDAC inhibitors. PARP inhibition further enhanced the efficacy of radiotherapy in ZMYND8 KO mIDH1 glioma cells. These findings indicate the impact of ZMYND8 in the maintenance of genomic integrity and repair of IR-induced DNA damage in mIDH1 glioma.

2022-12-19 | GSE220715 | GEO

Zinc Finger MYND-Type Containing 8 (ZMYND8) is epigenetically regulated in mutant Isocitrate Dehydrogenase 1 (IDH1) glioma to promote radioresistance [RNA-seq]

2022-12-19 | GSE220716 | 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

Effects of IDH1-R132H on mouse neural stem cells

Project description:Mouse neural stem cells were generated from conditional knock-in mice. Mutant IDH1 is conditionally expressed following expression of Cre-recombinase. Cre-recombinase was incorporated in vitro via adenoviral-Cre recombinase. Addtionally, adenoviral-GFP was also used to control for effects of adenoviral infection. D-2HG, the metabolic product of IDH1-R132H, was detected in cell lines post-cre transduction

2017-08-22 | GSE88828 | GEO

Differential gene expression in IDH1-R132H low grade glioma animal brain tumors brain in response to 20 Gy of radiation

Project description:IDH1-R132H is expressed in Low Grade Glioma (LGG) in combination with loss of function mutation in ATRX and TP53 genes. IDH1-R132H results in gain of function with production of 2-hydroxygluatrate, that in turn generates a hypermethylated phenotype in DNA and histone with consequences in epigenetic regulation of gene expression. Here we will compare the gene expression profile between IDH1-R132H and IDH1 Wt LLG moribund animal brain tumors and identify key genes responsible for the phenotype of this subtype of glioma.

2018-02-10 | GSE94902 | GEO

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