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

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

PROVIDER: PRJNA857306 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20071700_1.fastq.gz	Fastqsanger.gz
	SRR20071700_2.fastq.gz	Fastqsanger.gz
	SRR20071701_1.fastq.gz	Fastqsanger.gz
	SRR20071701_2.fastq.gz	Fastqsanger.gz
	SRR20071702_1.fastq.gz	Fastqsanger.gz

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

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.

2023-07-09 | GSE207830 | GEO

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

2023-07-09 | GSE207829 | 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 [methylation]

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

| PRJNA857305 | 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

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Genotyping by array of 297 adult-type diffuse gliomas comprise IDH-mutant astrocytomas, IDH-mutant 1p/19q codeleted oligodendrogliomas, and IDH-wildtype glioblastomas

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2024-12-24 | E-MTAB-13542 | biostudies-arrayexpress

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.

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TT-Seq captures the human transient transcriptome

Project description:A large portion of the genome is transcribed but many of the resulting RNAs live only transiently and can generally not be mapped. Here we develop transient transcriptome sequencing (TT-Seq), a protocol that maps transcriptionally active regions in a nearly uniform manner and allows for unbiased monitoring of cellular RNA synthesis activity. Application of TT-Seq to human K562 cells recovers stable mRNAs and long intergenic non-coding RNAs, and additionally maps over 10,000 transient RNAs including enhancer RNAs, antisense RNAs, promoter-associated upstream antisense and convergent RNAs. TT-Seq also provides RNA half-lives, and reveals that transient RNAs are short and lack U1 motifs and secondary structure. TT-Seq further uncovers transcription termination sites and reveals a universal DNA motif for RNA polymerase II release.

2016-06-03 | GSE75792 | GEO

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