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ATRX mutations mediate an immunogenic phenotype and macrophage infiltration in neuroblastoma.

ABSTRACT: ATRX mutations mediate an immunogenic phenotype and macrophage infiltration in neuroblastoma.

PROVIDER: PRJNA1160884 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30661333_1.fastq.gz	Fastqsanger.gz
	SRR30661333_2.fastq.gz	Fastqsanger.gz
	SRR30661334_1.fastq.gz	Fastqsanger.gz
	SRR30661334_2.fastq.gz	Fastqsanger.gz
	SRR30661335_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

ATRX mutations mediate an immunogenic phenotype and macrophage infiltration in neuroblastoma.

Project description:ATRX is one of the most frequently mutated genes in high-risk neuroblastoma. ATRX mutations are mutually exclusive with MYCN amplification and mark a recognizable patient subgroup, presenting in older children with chemotherapy-resistant, slowly progressive disease. The mechanisms underlying how ATRX mutations drive high-risk and difficult-to-treat neuroblastoma are still largely elusive. To unravel the role of ATRX in neuroblastoma, we generated isogenic neuroblastoma cell line models of both ATRX loss of-function and ATRX in-frame multi-exon deletions, representing different types of alterations found in patients. RNA-sequencing analysis consistently showed significant upregulation of pathways implicated in inflammatory responses and epithelial-to- mesenchymal transition in the ATRX-mutant cell lines. In vivo, ATRX mutations mediate macrophage recruitment in xenograft models. This was further confirmed in patient-derived xenograft models. In support of this, bioinformatic analysis of previously published neuroblastoma patient data sets revealed an immunogenic phenotype and higher score of macrophages (with no distinction between M1 and M2 macrophage populations) and dendritic cells, but not lymphocytes, in ATRX-mutant versus ATRX wildtype tumors. Histopathological assessment of diagnostic samples from patients with ATRX mutant disease confirmed these findings with more macrophage infiltration compared to MYCN-amplified tumors. In conclusion, these results highlight that in contrast to MYCN-amplified neuroblastoma, which is associated with a cold immune microenvironment, ATRX-mutated neuroblastoma is characterized by a distinct immunogenic phenotype.

2025-02-10 | GSE277158 | GEO

Two opposing gene expression patterns within ATRX aberrant neuroblastoma

Project description:To study the role of distinct ATRX aberrations in neuroblastoma we created isogenic ATRX aberrant models using CRISPR-Cas9 in several neuroblastoma cell lines and one tumoroid. We created ATRX knock-out models, ATRX in-frame exon 2-10 deletions and ATRX in-frame exon 2-13 deletions. Additionally, we included patient-derived models data (i.e. cell line data and one tumoroid).

2023-03-16 | GSE226770 | GEO

ATRX mutant neuroblastoma is sensitive to EZH2 inhibition via modulation of neuronal differentiation

Project description:We report on the characterization of ATRX in-frame fusion neuroblastoma and identify that ATRX IFF proteins re-locate from H3K9me3 enriched regions to active chromatin, such as the promoter of neural repressor REST. We further identify that REST is upregulated in ATRX IFF NB and that several neurogenesis and REST target genes are transcriptionally downregulated. Through ChIP-seq analysis, we observe that REST is bound to ATRX IFF Down genes, which have higher levels of H3K27me3. We further show that ATRX in-frame fusion neuroblastoma cells are sensitive to EZH2 inhibitors through de-repression of H3K27me3 bound neuronal function genes, includiing a subset of REST targets.

2019-10-15 | GSE100148 | GEO

Single cell RNA sequencing data of neuroblastoma infiltrated bone marrow

Project description:We report transcriptional analyses at single cell resolution of 16 bone marrow samples with and without neuroblastoma infiltration. Our samples span across several neuroblastoma models, including MYCN amplified, ATRX mutated, and sporadic (lacking either alteration).

2023-04-26 | GSE216155 | GEO

Single cell ATAC sequencing data of neuroblastoma infiltrated bone marrow

Project description:We report genome-wide ATAC-seq analyses at single cell resolution of 16 bone marrow samples with and without neuroblastoma infiltration. Our samples span across several neuroblastoma models, including MYCN amplified, ATRX mutated, and sporadic (lacking either alteration).

2023-04-26 | GSE216175 | GEO

Two opposing gene expression patterns within ATRX aberrant neuroblastoma

Project description:Two opposing gene expression patterns within ATRX aberrant neuroblastoma

| PRJNA941435 | ENA

MYCN Amplification and ATRX Mutations are Incompatible in Neuroblastoma

Project description:Age and stage of disease at diagnosis is associated with outcome in neuroblastoma. A previous study identified ATRX point mutations and in-frame deletions in older patients with stage 4 disease. To validate the frequency of ATRX mutations and assess the relation of mutations and known prognostic variables, we collaborated with the Children’s Oncology Group and sequenced the entire ATRX genomic locus in 475 neuroblastoma tumor samples to validate the frequency of ATRX mutations and assess the relation of mutations and known prognostic variables. Older age at diagnosis, stage 4 disease, and unfavorable histology were significantly associated with mutations in the ATRX gene; MYCN amplification was mutually exclusive from ATRX mutations. To directly test if ATRX mutations and MYCN amplification are incompatible in neuroblastoma, we mutated the ATRX gene in MYCN amplified neuroblastoma cell lines and ectopically expressed MYCN in ATRX mutant neuroblastoma cell lines. Both approaches showed that ATRX and MYCN amplification are incompatible in neuroblastoma in culture and in vivo. To gain a better understanding of the underlying molecular and cellular mechanisms of this incompatibility, we performed a series of experiments including telomere analysis, epigenetic profiling, electron microscopic analysis and metabolic profiling. We discovered that induction of MYCN expression in ATRX mutant neuroblastomas cells leads to metabolic reprogramming, mitochondrial dysfunction, increased reactive oxygen species and replicative stress. We propose that this leads to synthetic lethality in ATRX mutant neuroblastomas because of the underlying replicative stress in those cells as a result of dysfunction of this essential histone chaperone.

| EGAS00001003257 | EGA

The chromatin remodeler ATRX binds to atypical chromatin domains at the 3â exons of ZNF genes to preserve H3K9me3 enrichment

Project description:Here, we report that ATRX co-localizes with the H3K9-methyl transferase SETDB1 (also known as ESET), the co-repressor TRIM28 (also known as KAP1), and the transcription factor ZNF274 at 3â exons of Zinc Finger Genes (ZNFs) containing an atypical H3K9me3/H3K36me3 chromatin signature. Disruption of ATRX and ZNF274 leads to a significant reduction of H3K9me3, particularly at the 3â ZNF exons and other atypical chromatin regions, higher percentages of DNA damage, and defects in cell cycle. Taken together, our studies suggest that ATRX binds the 3â exons of ZNFs to maintain genomic stability through the regulation of their H3K9me3 levels XL-MNase ChIP-seq of ATRX was performed in the erythroleukemic cell line K562 and the Neuroblastoma cell line LAN6. Two independent replicates using different ATRX antibodies were performed in K562. Additionally, Native ChIP-seq of H3K9me3 in LAN6, ATRX WT and ATRX KO K562 cells was performed. Input samples were sequenced as control.

2016-04-05 | E-GEOD-70920 | biostudies-arrayexpress

Loss of p53 suppresses replication stress-induced DNA damage in ATRX-deficient neuroblastoma

Project description:To elucidate ATRX-dependent transcriptional alterations and their functional consequences, we performed a microarray analysis of Ctrl and ATRX KO NGP cells.

2022-09-08 | GSE183648 | GEO

Transcriptional analysis of ATRX deficiency in a M059J model

Project description:Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations in ATRX, a defining molecular alteration in IDH-mutant astrocytomas, have been implicated in dysfunctional immune signaling. However, little is known about the interplay between ATRX loss and IDH mutation on innate immunity. To explore this biology, we generated ATRX knockout glioma models in the presence and absence of the IDH1R132H mutation. ATRX-deficient glioma cells were sensitive to dsRNA-based innate immune agonism and exhibited impaired lethality and increased T-cell infiltration in vivo. However, the presence of IDH1R132H dampened baseline expression of key innate immune genes and cytokines in a manner restored by genetic and pharmacological IDH1R132H inhibition. IDH1R132H co-expression did not interfere with the ATRX KO-mediated sensitivity to dsRNA. Thus, ATRX loss primes cells for recognition of dsRNA, while IDH1R132H reversibly masks this priming. This work reveals innate immunity as a therapeutic vulnerability of astrocytoma.

2023-03-31 | GSE228243 | GEO

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