ATRX mutations mediate an immunogenic phenotype and macrophage infiltration in neuroblastoma.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1160884 | ENA |
REPOSITORIES: ENA
Similar Datasets
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
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
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
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
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
Project description:"Immunogenic subtype" characterised by macrophages infiltration predominantly comprise meningiomas in neurofibromatosis type 2 patients
| PRJNA972676 | ENA
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 | GSE228242 | GEO
Project description:Loss of the Atrx chromatin remodeling protein causes dysfunction and death of post-mitotic retinal interneurons in mice. Embryonic conditional deletion of Atrx from multipotent retinal progenitor cells results in the selective loss of the retinal inhibitory interneurons, namely amacrine and horizontal cells. The cell death occurs postnatally after the development of these cell types, peaking at postntal day 17 in the mouse retina. Identification of molecular factors and pathways that mediate the health and survival of these neurons may suggest novel therapeutic strategies for neuroprotection in ATR-X syndrome and other neurodegenerative diseases. We performed gene expression profiling of wildtype and Atrx conditional knockout mouse retina tissues to identify putative targets of Atrx and molecular pathways that underlie the neurodegenerative phenotype.
2016-09-09 | GSE78877 | GEO
Project description:The chromatin regulator ATRX is inactivated in large subsets of adult and pediatric glioma. Whether and how ATRX deficiency promotes oncogenesis by epigenomic dysregulation remains unclear. We found that Atrx loss, especially when coupled with Tp53 inactivation, promoted cell motility and modulated differentiation state in primary murine neuroepithelial progenitors, recapitulating characteristic disease phenotypes and molecular features. Moreover, Atrx deficiency induced widespread shifts in chromatin accessibility, histone composition, and gene transcription at vacant Atrx binding sites distributed across the genome. Finally, target genes mediating Atrx-deficient phenotypes in vitro exhibited similarly selective misexpression in ATRX-mutant human glioma tissues and cell lines. These findings demonstrate that, in appropriate physiological contexts, ATRX deficiency and its epigenomic sequelae are sufficient to induce disease-defining oncogenic phenotypes.
2017-12-31 | GSE100462 | GEO
Project description:Heterochromatin in the eukaryotic genome is rigorously controlled by the concerted action of protein factors and RNAs. Here, we investigate the RNA binding function of ATRX, a chromatin remodeler with roles in silencing of repetitive regions of the genome and in recruitment of the polycomb repressive complex 2 (PRC2). We identify ATRX RNA binding regions (RBRs) and discover that the major ATRX RBR lies within the N-terminal region of the protein, distinct from its PHD and helicase domains. Deletion of this ATRX RBR (ATRXRBR) compromises ATRX interactions with RNAs in vitro and in vivo and alters its chromatin binding properties. Genome-wide studies reveal that loss of RNA interactions results in a redistribution of ATRX on chromatin. Finally, our studies identify a role for ATRX-RNA interactions in regulating PRC2 localization to a subset of polycomb target genes.
2020-03-09 | PXD017806 | Pride