Transcriptional analysis of ATRX deficiency in a CT2A glioma model
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ABSTRACT:
PROVIDER: PRJNA949116 | ENA |
REPOSITORIES: ENA
Similar Datasets
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:Transcriptional analysis of co-occuring ATRX deficiency and IDH1 mutation in a CT2A glioma model
| PRJNA948443 | 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.
2023-03-29 | GSE228181 | 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: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 | GSE100464 | 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 | GSE100463 | 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 | GSE100461 | GEO
Project description:A common cornerstone of preclinical cancer research is the use of syngeneic orthotopic murine tumors as immunocompetent models of human cancers. For glioblastoma research efforts, the GL261 and CT2A lines are frequently used. We systematically characterized these two lines to decipher the cell-intrinsic mechanisms that drive immuno-resistance in CT2A and to define the aspects of human cancer biology that the lines best model. We show that, despite sharing a few canonical genetic or histologic features of human glioblastoma, the transcriptional profiles of GL261 and CT2A tumours most closely resembled those of glioblastomas. CT2A additionally resembled other cancer types transcriptionally, including melanoma. CT2A displayed mesenchymal differentiation, upregulated angiogenesis, and multiple defects in antigen presentation machinery and interferon response pathways. Loss of MHC class I expression was restored in CT2A by interferon-γ treatment, explaining in part the modest efficacy of some immunotherapy combinations for CT2A. Our findings indicate that CT2A may serve as a robust preclinical solid tumor model of adaptive immune resistance.
2023-12-19 | PXD036720 | Pride
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:Methylation profiling of SF188 paediatric high grade glioma cell line isogenic clones carrying CRISR/Cas9 frameshift deletions in ATRX
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