Lysine acetylation restricts mutant IDH2 activity to optimize transformation in AML cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA725900 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14350400_1.fastq.gz | Fastqsanger.gz | |||
| SRR14350400_2.fastq.gz | Fastqsanger.gz | |||
| SRR14350401_1.fastq.gz | Fastqsanger.gz | |||
| SRR14350401_2.fastq.gz | Fastqsanger.gz | |||
| SRR14350402_1.fastq.gz | Fastqsanger.gz |
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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: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 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.
| S-EPMC8455438 | biostudies-literature
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: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:We assessed global gene expression changes 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.
2017-08-04 | GSE60050 | GEO
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
Project description:Gene profiling of human primary fibroblasts treated with IDH2 inhibitor or vehicle (DMSO), for 3 or 6 days
2023-03-22 | E-MTAB-12637 | biostudies-arrayexpress
Project description:We compared the DNA methylation profiles of 12 intrahepatic cholangiocarcinomas harboring mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, with 28 intrahepatic cholangiocarcinomas without these mutations. We profiled these samples with the Illumina HumanMethylation450 BeadChip, and characterized over 2,000 genes that were hypermethylated in tumors with mutations in IDH1 or IDH2.
2012-06-11 | GSE32079 | GEO
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