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Induction of sarcomas by mutant IDH2

ABSTRACT: 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..

ORGANISM(S): Homo sapiens

PROVIDER: GSE50539 | GEO | 2013/10/21

SECONDARY ACCESSION(S): PRJNA217989

REPOSITORIES: GEO

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Induction of sarcomas by mutant IDH2

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

IDH2 mutation induced histone and DNA hypermethylation is progressively reversed by small molecule inhibition

Project description:Mutations of IDH1 (R132) and IDH2 (R172 and R140), which produce an oncometabolite 2-hydroxyglutarate (2HG), have been identified in several tumors including acute myeloid leukemia (AML). Recent studies have shown that expression of the IDH mutant enzymes results in high levels of 2HG and a block in cellular differentiation that can be reversed with IDH-mutant specific small molecule inhibitors. To further understand the role of IDH mutations in cancer, we conducted mechanistic studies in the TF-1/IDH2 R140Q erythroleukemia model system and found that IDH2 mutant expression caused both histone and genomic DNA methylation changes that can be reversed when IDH2 mutant activity is inhibited. Specifically, histone hypermethylation is rapidly reversed within days whereas reversal of DNA hypermethylation proceeds in a progressive manner over the course of weeks. Pathway enrichment analysis revealed several pathways involved in tumorigenesis of leukemia and lymphoma, indicating a selective modulation of relevant cancer genes by IDH mutations. As methylation of DNA and histones is closely linked to mRNA expression and differentiation, these results indicate that IDH2 mutant inhibition may function as a cancer therapy via short-term histone demethylation and long-term DNA demethylation at genes involved in differentiation and tumorigenesis. TF-1 cells with and without IDH2/R140Q expression were treated with DMSO or AGI-6780, an inhibitor of IDH2/R140Q for 7 to 28 days. Genomic DNA was extracted and analyzed by the Illumina 450k Methylation array.

2014-11-19 | E-GEOD-51352 | biostudies-arrayexpress

IDH2 mutation induced histone and DNA hypermethylation is progressively reversed by small molecule inhibition

2014-11-19 | GSE51352 | 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

Serine biosynthesis is a metabolic vulnerability in IDH2-driven breast cancer progression

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

A personalized medicine approach identifies enasidenib as an efficient treatment for IDH2 mutant chondrosarcoma [MethArray_2days]

Project description:The heterogenous genomic nature of most sarcoma subtypes makes them especially indicated for personalized treatment approaches. Here, we developed a personalized medicine strategy based in the use of patient-derived cell lines as a drug-testing platform. Targeted sequencing of a panel of cancer-related genes in these models revealed the presence of IDH1 and IDH2 mutations in two chondrosarcomas. Mutant IDH (mIDH) enzymes produce the oncometabolite 2-HG which contributes to driving tumor growth. Thus, we treated several chondrosarcoma models with specific mIDH1/2 inhibitors. Among these treatments, only the mIDH2 inhibitor enasidenib was able to decrease 2-HG levels and to efficiently reduce the viability of mIDH2 chondrosarcoma cells. Importantly, oral administration of enasidenib in xenografted mice resulted in a complete abrogation of tumor growth. Enasidenib induced a profound remodeling of the transcriptomic landscape not associated to changes in the 5mC methylation levels and its anti-tumor effects were associated to the repression of proliferative pathways such as those controlled by E2F factors. Overall, this work provides the first preclinical evidence for the use of enasidenib to treat mIDH2 chondrosarcomas.

2024-03-11 | GSE235697 | GEO

A personalized medicine approach identifies enasidenib as an efficient treatment for IDH2 mutant chondrosarcoma [RNAseq_Enasidenib_L2975_SW1353]

2024-03-13 | GSE261434 | GEO

A personalized medicine approach identifies enasidenib as an efficient treatment for IDH2 mutant chondrosarcoma [MethArray_5days]

2024-03-12 | GSE261421 | GEO

Global methylation alteration in Dnmt3aKO-Idh2 mutant double mutant HSPCs

Project description:We investigated DNA methylation alterations in Dnmt3aKO-Idh2 mutant HSPCs in comparison with the megarkaryocyte erythroid progenitor (MEP) and Granulocyte Macrophage Progenitor(GMP) of Dnmt3a knockout, Idh2 mutant, WT genotypes. We generated an average of 17.42 million reads per sample (12.17 - 24.53 million) of which an average of 16.39 million could be mapped to the mm9 genome (11.74 - 23.73 million). We achieved an average CpG coverage depth of 27.88-fold (19.52 - 35.89-fold) and average bisulfite conversion efficiency of 99.61% (98.43 - 99.94%).

2017-08-04 | GSE60054 | GEO

Combination targeted therapy to disrupt aberrant oncogenic signaling and reverse epigenetic dysfunction in IDH2- and TET2-mutant acute myeloid leukemia (RRBS)

Project description:Genomic studies in acute myeloid leukemias (AML) have identified mutations which drive altered DNA methylation, including TET2 and IDH. Functional studies have shown these mutations contribute to transformation, although how these mutations impact the response to epigenetic therapies is not fully delineated. Here we show AMLs with TET2/IDH2 mutations combined with FLT3ITD mutations are specifically sensitive to 5-Azacytidine or to the IDH2 inhibitor AG-221, respectively. 5-Azacytidine/AG-221 therapies induced a reduction in leukemic blasts and in stem/progenitor expansion, with attenuation of aberrant DNA hypermethylation. These therapeutic benefits were achieved through restoration of differentiation, such that normalized hematopoiesis was derived from mutant cells. Consistent with these data, at the time of clinical response to 5-Azacytidine or AG-221, most patients had mutant-derived hematopoiesis. By contrast, combined AG-221/5-Azacytidine plus FLT3 inhibition reduced disease burden and reversed epigenetic dysfunction. Our studies suggest combined targeting of signaling and epigenetic pathways can increase therapeutic response in AML.

2017-02-25 | GSE78690 | GEO

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