Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE24505 | GEO | 2010/12/03
SECONDARY ACCESSION(S): PRJNA132611
REPOSITORIES: GEO
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Project description:Cancer-associated IDH mutations are characterized by neomorphic enzyme activity and resultant 2 hydroxyglutarate (2HG) production. Mutational and epigenetic profiling of a large AML patient cohort revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and a specific hypermethylation signature. Furthermore, expression of 2HG-producing IDH alleles in cells rapidly induced global DNA hypermethylation. In the AML cohort, IDH1/2 mutations were mutually exclusive with mutations in the α-ketoglutarate-dependent enzyme TET2, and TET2 loss-of function mutations associated with similar epigenetic defects as IDH1/2 mutants. Consistent with these genetic and epigenetic data, expression of IDH mutants impaired TET2 catalytic function in cells. Finally, either expression of mutant IDH1/2 or Tet2 depletion impaired hematopoietic differentiation and increased stem cell marker expression, suggesting a shared pro-leukemogenic effect. DNA methylation and gene expression profiling in IDH1/2 mutant vs. IDH1/2 wild-type AML
2010-12-03 | E-GEOD-24505 | biostudies-arrayexpress
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: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.
2014-11-19 | GSE51352 | GEO
Project description:Oncogenic mutations in isocitrate dehydrogenase (IDH)-1 and -2 occur in a wide range of cancers, including acute myeloid leukemias (AMLs) and gliomas1-3. Mutant IDH enzymes convert 2-oxoglutarate (2OG) to (R)-2-hydroxyglutarate [(R)-2HG]4,5, an oncometabolite that induces cellular transformation by dysregulating 2OG-dependent enzymes. The only direct target of (R)-2HG known to contribute to transformation is the 5-methylcytosine hydroxylase TET2, and there is ample evidence to suggest that (R)-2HG drives leukemogenesis at least in part by inhibiting TET26,7. However, IDH mutations, but not TET2 mutations, are specifically associated with aggressive hematologic diseases, suggesting that (R)-2HG has targets other than TET2 that contribute to mutant IDH-mediated transformation. Here, we report that (R)-2HG directly inhibits KDM5 histone lysine demethylases in IDH-mutant AMLs and gliomas to induce cellular transformation. These studies provide a functional link between dysregulation of histone lysine methylation and tumorigenesis in IDH-mutant cancers.
2023-03-01 | GSE184611 | GEO
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
Project description:Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation in mutant leukemic blasts and may provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, most responders eventually relapse. To understand the molecular underpinnings of clinical resistance, we performed multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 68 IDH1/IDH2-mutant AML patients treated with IDH inhibitors (IDHi), and described the evolution of AML genome and epigenome during the therapy and its association with clinical response and relapse. Co-occurrence of mutations in RUNX1/CEBPA or RAS-RTK pathway genes were associated with poor response to IDHi. The same group of mutations were also frequently selected or acquired at relapse. In addition, acquired mutations in BCOR, reciprocal IDH gene, and TET2 were also implicated at relapse. DNA methylation changes largely mirrored plasma 2HG dynamics and had little association with clinical response to IDHi. The mapping of mutation dynamics and methylation changes in longitudinal samples revealed the interplay between AML genome and epigenome with IDHi therapy. While the alteration in RAS-RTK signaling genes and RUNX1/CEBPA were the key molecular pathways involved in clinical resistance to IDHi, diverse molecular pathways were involved in IDHi resistance. The data highlights the role of clonal heterogeneity in therapeutic resistance in AML and implicates opportunities for novel combination strategies.
2021-03-11 | GSE153348 | GEO
Project description:Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation in mutant leukemic blasts and may provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, most responders eventually relapse. To understand the molecular underpinnings of clinical resistance, we performed multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 68 IDH1/IDH2-mutant AML patients treated with IDH inhibitors (IDHi), and described the evolution of AML genome and epigenome during the therapy and its association with clinical response and relapse. Co-occurrence of mutations in RUNX1/CEBPA or RAS-RTK pathway genes were associated with poor response to IDHi. The same group of mutations were also frequently selected or acquired at relapse. In addition, acquired mutations in BCOR, reciprocal IDH gene, and TET2 were also implicated at relapse. DNA methylation changes largely mirrored plasma 2HG dynamics and had little association with clinical response to IDHi. The mapping of mutation dynamics and methylation changes in longitudinal samples revealed the interplay between AML genome and epigenome with IDHi therapy. While the alteration in RAS-RTK signaling genes and RUNX1/CEBPA were the key molecular pathways involved in clinical resistance to IDHi, diverse molecular pathways were involved in IDHi resistance. The data highlights the role of clonal heterogeneity in therapeutic resistance in AML and implicates opportunities for novel combination strategies.
2021-03-11 | GSE153347 | GEO
Project description:Isocitrate dehydrogenases 1 and 2 (IDH1/2) are recurrently mutated in acute myeloid leukemia (AML), but their mechanistic role in leukemogenesis is poorly understood. The inhibition of TET enzymes by D-2-hydroxyglutarate (D-2-HG), which is produced by mutant IDH1/2 (mIDH1/2), has been suggested to promote epigenetic deregulation during tumorigenesis. In addition, mIDH also induces a differentiation block in various cell culture and mouse models. Here we analyze the genomic methylation patterns of AML patients with mIDH using Infinium 450K data from a large AML cohort and found that mIDH is associated with pronounced DNA hypermethylation at tens of thousands of CpGs. Interestingly, however, myeloid leukemia cells overexpressing mIDH, cells that were cultured in the presence of D-2-HG or TET2 mutant AML patients did not show similar methylation changes. In further analyses, we also characterized the methylation landscapes of myeloid progenitor cells and analyzed their relationship to mIDH-associated hypermethylation. Our findings identify the differentiation state of myeloid cells, rather than inhibition of TET-mediated DNA demethylation, as a major factor of mIDH-associated hypermethylation in AML. Furthermore, our results are also important for understanding the mode of action of currently developed mIDH inhibitors.
2017-09-15 | E-MTAB-6059 | biostudies-arrayexpress
Project description:Gene expression of mouse hepatoblasts (HBs) expressing IDH1 WT, IDH1 R132C, IDH2 WT, R172K and empty vector controls (N=2 cultures for each condition) grown on collagen-coated plates and IDH1 R132C and empty vector controls on uncoated plates were evaluated using Affymetrix Mouse 430Av2 DNA microarrays that were processed at the Dana-Farber Cancer Institute core facility (http://macf-web.dfci.harvard.edu/) using their standard protocol. Mutations in Isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly primary liver cancer. Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert alphaketoglutarate (aKG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple aKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellular matrix maturation. However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear. Here we show that mutant IDH blocks primary liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF4a, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models (GEMMs) expressing mutant IDH in the adult liver show aberrant response to hepatic injury, characterized by HNF4a silencing, impaired hepatocyte differentiation and markedly elevated levels of cell proliferation. Moreover, mutant IDH and activated Kras, genetic alterations that co-exist in a subset of human IHCCs, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic IHCC. These studies provide a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis and present a novel GEMM of IDH-driven malignancy. Gene expression of HBs expressing IDH1 WT, IDH1 R132C, IDH2 WT, R172K and empty vector controls under a doxycycline-inducible system (N=2 cultures for each condition) grown on collagen-coated plates and IDH1 R132C and empty vector controls on uncoated plates were evaluated using Affymetrix Mouse 430Av2 DNA microarrays.
2014-04-30 | E-GEOD-57002 | biostudies-arrayexpress
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