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

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

PROVIDER: PRJNA857302 | 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 [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]

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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 [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.

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

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RNA-seq of NK cells from blood samples of HV and AML patients

Project description:CD56neg CD16+ Natural Killer (NK) cells have been reported to expand in chronic diseases and acute myeloid leukemia (AML). However, their biological role is still unclear. Using bulk RNA-sequencing, we compared gene expression profile of CD56neg CD16+ NK cells with conventional CD56bright, CD56dim CD16- and CD56dim CD16+ NK cells from blood samples of HV and AML patients. RNA-seq unveiled that CD56neg CD16+ NK cells were mature circulating NK cells with functional capacities. Taken together, our results suggest that CD56neg CD16+ NK cells are a relevant target for future NK-cell-based immunotherapies.

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