RNA-seq analysis of MEF cells with stably overexpression of IDH2 mutation and MEF cells treated with 2-HG
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA748020 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15192252.fastq.gz | Fastqsanger.gz | |||
| SRR15192253.fastq.gz | Fastqsanger.gz | |||
| SRR15192254.fastq.gz | Fastqsanger.gz | |||
| SRR15192255.fastq.gz | Fastqsanger.gz | |||
| SRR15192256.fastq.gz | Fastqsanger.gz |
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Project description:Isocitrate dehydrogenase 2 (IDH2) mutations and its key effector 2-hydroxyglutarate (2-HG) have been reported to promote oncogenesis in various human cancers. To elucidate molecular mechanism(s) associated with IDH2 mutations, we established mouse embryonic fibroblasts (MEF) cells stably expressing cancer-associated IDH2R172S mutation and treated MEF cells with or without 2-HG. The expression of genes in these cells were analyzed by RNA-seq.
2021-09-13 | GSE180369 | GEO
Project description:Mutations in IDH1 and IDH2 are frequently observed in various cancers, including acute myeloid leukemia (AML). Mutant IDHs convert α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), which dysregulates a set ofα-KG-dependent dioxygenases. To determine whether mutant IDHs are valid targets for cancer therapy, we established a mouse AML model harboring an IDH2 mutation by transplanting mice with nucleophosmin1 (NPM1)+/- mouse hematopoietic stem/progenitor cells that had been co-transduced with four mutant genes (NPMc, IDH2/R140Q, DNMT3A/R882H and FLT3/ITD) that frequently occur simultaneously in human AML patients. IDH2/R140Q is necessary for the engraftment or survival of NPMc+ cells in vivo. Gene-expression analysis indicated that NPMc increased the expression of Hoxa9, and that IDH2/R140Q increased the level of Meis1 and activated the hypoxia pathway in AML cells. Conditional deletion of IDH2/R140Q blocked 2-HG production and maintenance of leukemia stem cells, resulting in survival of the AML mice. IDH2/R140Q reversibly decreased the levels of 5hmC modification and gene expression at some differentiation inducing genes (Ebf1, Pax5 and Spib). These results indicate that the IDH2 mutation is critical for the development and maintenance of AML stem cells, and that mutant IDHs are promising targets for anticancer therapy.
2015-03-25 | GSE63618 | GEO
Project description:Mutations in IDH1 and IDH2 are frequently observed in various cancers, including acute myeloid leukemia (AML). Mutant IDHs convert α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), which dysregulates a set ofα-KG-dependent dioxygenases. To determine whether mutant IDHs are valid targets for cancer therapy, we established a mouse AML model harboring an IDH2 mutation by transplanting mice with nucleophosmin1 (NPM1)+/- mouse hematopoietic stem/progenitor cells that had been co-transduced with four mutant genes (NPMc, IDH2/R140Q, DNMT3A/R882H and FLT3/ITD) that frequently occur simultaneously in human AML patients. IDH2/R140Q is necessary for the engraftment or survival of NPMc+ cells in vivo. Gene-expression analysis indicated that NPMc increased the expression of Hoxa9, and that IDH2/R140Q increased the level of Meis1 and activated the hypoxia pathway in AML cells. Conditional deletion of IDH2/R140Q blocked 2-HG production and maintenance of leukemia stem cells, resulting in survival of the AML mice. IDH2/R140Q reversibly decreased the levels of 5hmC modification and gene expression at some differentiation inducing genes (Ebf1, Pax5 and Spib). These results indicate that the IDH2 mutation is critical for the development and maintenance of AML stem cells, and that mutant IDHs are promising targets for anticancer therapy.
2015-03-25 | GSE63635 | GEO
Project description:Cancer-specific metabolic phenotypes and their vulnerabilities are one among the viable areas of cancer research. We studied the association of breast cancer subtypes with different metabolic phenotypes and identified isocitrate dehydrogenase 2 (IDH2) as a key player in triple negative breast cancer (TNBC) and HER2. Functional assays combined with mass spectrometry-based analyses reveal the oncogenic role of IDH2 in cell proliferation, anchorage-independent growth, glycolysis, mitochondrial respiration and antioxidant defense. Genome-scale metabolic modeling identified PHGDH and PSAT1 as the synthetic dosage lethal (SDL) partners of IDH2. In agreement, CRISPR-Cas9 knockout of PHGDH and PSAT1 showed the essentiality of serine biosynthesis proteins in IDH2-high cells. The clinical significance of the SDL interaction showed patients with IDH2-high/PHGDH-low have better survival than IDH2-high/PHGDH-high. Furthermore, we show the efficacy of PHGDH inhibitors in treating IDH2-high cells in vitro and in in vivo. Altogether, our study creates a new link between two known cancer regulators and emphasizes PHGDH as a promising target for TNBC with IDH2 overexpression.
2021-01-04 | PXD023142 | Pride
Project description:Mutant isocitrate dehydrogenase (IDH) 1 and 2 play a pathogenic role in cancers including acute myeloid leukemia (AML) by producing oncometabolite 2- hydroxyglutarate (2-HG) . We recently reported that tyrosine phosphorylation activates IDH1 R132H mutant in AML cells. Here we show that, surprisingly, mutant IDH2 (mIDH2) R140Q commonly has K413-acetylation, which negatively regulates mIDH2 activity in human AML cells by attenuating dimerization and blocking binding of substrate (α-ketoglutarate) and cofactor (NADPH). Mechanistically, K413-acetylation of mitochondrial mIDH2 is achieved through a series of hierarchical phosphorylation events mediated by tyrosine kinase FLT3, which phosphorylates mIDH2 to recruit upstream mitochondrial acetyltransferase ACAT1 and simultaneously activates ACAT1 and inhibits upstream mitochondrial deacetylase SIRT3 through tyrosine- phosphorylation. Moreover, we found that the intrinsic enzyme activity of mIDH2 is much higher than mIDH1, thus the inhibitory K413-acetylation optimizes leukemogenic ability of mIDH2 in AML cells by both producing sufficient 2-HG for transformation and avoiding cytotoxic accumulation of intracellular 2-HG.
2021-09-29 | GSE173531 | GEO
Project description:Herein we developed a multigenic AML model with inducible expression of IDH2R140Q and constitutive expression of mutant DNMT3AR882H and NRASG12D. Using genetic de-induction and the first-in-class IDH2 inhibitor AG-221, we demonstrate that despite the presence of multiple oncogenic lesions, AML cells expressing mutant IDH2 depend on continued production of 2-HG to maintain their leukemic potential. Moreover, by comparing pharmacological inhibition and genetic depletion of IDH2R140Q we validate AG-221 as a highly on target inhibitor and identify key downstream pathways including GATA1 that are critical for disease maintenance.
2017-04-15 | GSE97078 | GEO
Project description:More than 50% of patients with chondrosarcomas exhibit gain-of-function mutations in either isocitrate dehydrogenase 1 (IDH1) or IDH2. In this study, we performed genome-wide CpG methylation sequencing of chondrosarcoma biopsies and found that IDH mutations were associated with DNA hypermethylation at CpG islands but not other genomic regions. Regions of CpG island hypermethylation were enriched for genes implicated in stem cell maintenance/differentiation and lineage specification. In murine 10T1/2 mesenchymal 20 progenitor cells, expression of mutant IDH2 led to DNA hypermethylation and an impairment in differentiation that could be reversed by treatment with DNA-hypomethylating agents. Introduction of mutant IDH2 also induced loss of contact inhibition and generated undifferentiated sarcomas in vivo. The oncogenic potential of mutant IDH2 correlated with the ability to produce 2-hydroxyglutarate. Together, these data demonstrate that neomorphic IDH2 mutations can be oncogenic in mesenchymal cells.. RRBS sequencing of (1) IDH wild type and mutant human chondrosarcomas, (2) isogenic cell lines expressing wild-type or mutant IDH.
2013-10-21 | E-GEOD-50539 | biostudies-arrayexpress
Project description:More than 50% of patients with chondrosarcomas exhibit gain-of-function mutations in either isocitrate dehydrogenase 1 (IDH1) or IDH2. In this study, we performed genome-wide CpG methylation sequencing of chondrosarcoma biopsies and found that IDH mutations were associated with DNA hypermethylation at CpG islands but not other genomic regions. Regions of CpG island hypermethylation were enriched for genes implicated in stem cell maintenance/differentiation and lineage specification. In murine 10T1/2 mesenchymal 20 progenitor cells, expression of mutant IDH2 led to DNA hypermethylation and an impairment in differentiation that could be reversed by treatment with DNA-hypomethylating agents. Introduction of mutant IDH2 also induced loss of contact inhibition and generated undifferentiated sarcomas in vivo. The oncogenic potential of mutant IDH2 correlated with the ability to produce 2-hydroxyglutarate. Together, these data demonstrate that neomorphic IDH2 mutations can be oncogenic in mesenchymal cells..
2013-10-21 | GSE50539 | GEO
Project description:RNAseq anaysis of RTF2 MEF cells
| PRJNA638152 | ENA
Project description:Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) have been discovered in several cancer types and cause the neurometabolic syndrome D2-Hydroxyglutaric aciduria (D2HGA). The mutant enzymes exhibit neomorphic activity resulting in production of D2- hydroxyglutaric acid (D-2HG). To study the pathophysiological consequences of the accumulation of D2-HG, we generated transgenic mice with conditionally activated IDH2R140Q and IDH2R172K alleles. Global induction of mutant IDH2 expression in adults resulted in dilated cardiomyopathy, white matter abnormalities throughout the central nervous system (CNS), and muscular dystrophy. Embryonic activation of mutant IDH2 resulted in more pronounced phenotypes, including runting, hydrocephalus, and shortened life span—recapitulating the abnormalities observed in D2HGA patients. The diseased hearts exhibited mitochondrial damage and glycogen accumulation with a concordant upregulation of genes involved in glycogen biosynthesis. Notably, mild cardiac hypertrophy was also observed in nude mice implanted with IDH2R140Q expressing xenografts, suggesting that 2HG may potentially act in a paracrine fashion. Finally, we show that silencing of IDH2R140Q in mice with an inducible transgene restores heart function by lowering 2HG levels. Together, these findings indicate that inhibitors of mutant IDH2 may be beneficial in the treatment of D2HGA and suggest that 2HG produced by IDH mutant tumors has the potential to provoke a paraneoplastic condition. We have performed microarray expression profiling of hearts from IDH2 mutant and control mice.
2014-03-01 | E-GEOD-54838 | biostudies-arrayexpress