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Perturbed epigenetic transcriptional regulation in AML with IDH mutations causes increased susceptibility to NK cells [methylation]

ABSTRACT: Perturbed epigenetic transcriptional regulation in AML with IDH mutations causes increased susceptibility to NK cells [methylation]

PROVIDER: PRJNA857305 | ENA |

REPOSITORIES: ENA

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Perturbed epigenetic transcriptional regulation in AML with IDH mutations causes increased susceptibility to NK cells [methylation]

Project description:IDH mutations are found in 20% of acute myeloid leukemia (AML) patients. IDH inhibitors (IDHi) have emerged as a novel treatment option. However, only 30-40% of patients respond to single drug treatment and there is an unmet need for improvement as well as identifying alternative treatment options. The overall aim of this study was therefore to gain deeper insights into the molecular signatures of IDH mutations, the effects of IDHi as well as to identify a molecular vulnerability to tailor novel therapies for AML patients with IDH mutations. Here, we have characterized the transcriptional and epigenetic landscape before and after treatment with IDH2i AG-221, using an IDH2 mutated AML cell line model and AML patient cohorts. We discovered decreased DNA hydroxymethylation in IDH2 mutated AML cells, particular in enhancers and a perturbed transcriptional regulatory network involving myeloid transcription factors. In addition, hypermethylation of the HLA I cluster caused a dramatic down-regulation of HLA genes, triggering an enhanced natural killer (NK) cell activation, and displayed an increased susceptibility to NK cell mediated killing. These responses were reverted when the AML cells were pre-exposed to IFN-gamma, resulting in up-regulation of cell surface HLA class I. Finally, analyses of DNA methylation data from IDHi-treated patients showed that non-responders continued to harbor hypermethylation in HLA class I genes, suggesting maintained susceptibility to NK cells. In conclusion, this study provides new insights into the perturbed epigenetic and transcriptional regulation in IDH mutated AML and shed light on a potential strategy for personalized medicine in AML. Methylation/hydroxymethylation profiling by array

2023-07-09 | GSE207829 | GEO

Perturbed epigenetic transcriptional regulation in AML with IDH mutations causes increased susceptibility to NK cells [TT-Seq]

2023-07-09 | GSE207830 | GEO

Perturbed epigenetic transcriptional regulation in AML with IDH mutations causes increased susceptibility to NK cells

Project description:Perturbed epigenetic transcriptional regulation in AML with IDH mutations causes increased susceptibility to NK cells

| PRJNA857302 | ENA

Perturbed epigenetic transcriptional regulation in AML with IDH mutations causes increased susceptibility to NK cells [TT-Seq]

Project description:Perturbed epigenetic transcriptional regulation in AML with IDH mutations causes increased susceptibility to NK cells [TT-Seq]

| PRJNA857306 | ENA

Perturbed epigenetic transcriptional regulation in AML with IDH mutations causes increased susceptibility to NK cells.

Project description:Isocitrate dehydrogenase (IDH) mutations are found in 20% of acute myeloid leukemia (AML) patients. However, only 30-40% of the patients respond to IDH inhibitors (IDHi). We aimed to identify a molecular vulnerability to tailor novel therapies for AML patients with IDH mutations. We characterized the transcriptional and epigenetic landscape with the IDH2i AG-221, using an IDH2 mutated AML cell line model and AML patient cohorts, and discovered a perturbed transcriptional regulatory network involving myeloid transcription factors that were partly restored after AG-221 treatment. In addition, hypermethylation of the HLA cluster caused a down-regulation of HLA class I genes, triggering an enhanced natural killer (NK) cell activation and an increased susceptibility to NK cell-mediated responses. Finally, analyses of DNA methylation data from IDHi-treated patients showed that non-responders still harbored hypermethylation in HLA class I genes. In conclusion, this study provides new insights suggesting that IDH mutated AML is particularly sensitive to NK cell-based personalized immunotherapy.

| S-EPMC10457197 | biostudies-literature

Perturbed epigenetic transcriptional regulation in AML with IDH mutations causes increased susceptibility to NK cells

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-07-09 | GSE207831 | GEO

Safety and Efficacy of NEO212 in Patients With Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype or Brain Metastasis

Project description:This multi-site, Phase 1/2 clinical trial is an open-label study to identify the safety, pharmacokinetics, and efficacy of a repeated dose regimen of NEO212 for the treatment of patients with radiographically-confirmed progression of Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype, and the safety, pharmacokinetics and efficacy of a repeated dose regimen of NEO212 when given with select SOC for the treatment of solid tumor patients with radiographically confirmed uncontrolled brain metastasis. The study will have three phases, Phase 1, Phase 2a and Phase 2b.

| 92735 | ecrin-mdr-crc

Expression from hemocytes misexpressing Idh-R195H vs. controls

Project description:Expression profile for hemocytes from hml-Gal4, UAS-2xEGFP larvae were compared to hemocytes from hml-Gal4, UAS-2xEGFP; UAS-Idh-R195H larvae We sought to determine which genes and pathways were upregulated or downregulated in hemocytes expressing Idh-R195H, the Drosophila homolog of the human cancer-associated IDH1-R132H mutant, in vivo. We sought to obtain homogeneous populations of hemocytes from each genotype. We compared larvae expressing Idh-R195H from the hml-Gal4 driver to larvae with the hml-Gal4 driver alone.

2014-10-03 | E-GEOD-62008 | biostudies-arrayexpress

Insulator dysfunction and oncogene activation in IDH mutant gliomas

Project description:Gain-of-function IDH mutations define major clinical and prognostic classes of gliomas. Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylase enzymes, including the TET family of 5'-methylcytosine hydroxylases. TET enzymes are critical for the dynamic regulation of DNA methylation. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP), though the functional significance of this altered epigenetic state remains unclear. Here we show that IDH1 mutant gliomas exhibit hyper-methylation at CTCF binding sites, leading to reduced binding of this methylation-sensitive insulator protein. Loss of CTCF binding is associated with a loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to aberrantly interact with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with demethylating agent partially restores insulator function and reduces PDGFRA expression. Conversely, CRISPR-mediated disruption of the CTCF binding sequence in IDH wildtype gliomaspheres induces PDGFRA expression and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression. CTCF occupancy characterization and histone H3K27 acetylation profiling in IDH1 mutant and wild-type glioma patient specimens and culture models. ChIP-seq raw data is to be made available through dbGaP (controlled access) due to patient privacy concerns.

2015-12-23 | E-GEOD-70991 | biostudies-arrayexpress

Gene expression changes in IDH mutant or IDH wildtype gliomas treated with All-trans Retinoic Acid

Project description:IDH mutant cells are deficient in retinoic acid production, which impacts downstream gene expression and pathways. We looked at the effect of supplementing IDH mutant glioma cells with ATRA on gene expression and downstream pathways. We compared gene expression changes with IDH WT cells that were also treated with ATRA

2019-12-11 | GSE141789 | GEO

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