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

Study ID Alternative Stable ID Type
EGAS00001002507 Other

Study Description

Mutations and structural alterations of the SWI/SNF-like chromatin remodeler ATRX have been reported at high frequency in a number of adult and pediatric tumors1. However, the consequences of ATRX (Alpha Thalassemia/Mental Retardation, X-linked) mutations in cancer and their underlying epigenetic sensitivities remain ill defined. Particularly intriguing are the large N-terminal deletions of ATRX in neuroblastoma that generate in-frame fusion (IFF) proteins1–3 devoid of key chromatin interaction domains. Here we demonstrate that neuroblastoma cells harbouring ATRX IFFs have distinct gene expression programs compared to neuroblastoma cells that are wild type for ATRX. This is due in part to H3K27me3-mediated silencing of REST (RE1 Silencing Transcription Factor) target genes involved in neuronal differentiation. In turn, we find that ATRX IFF cells display exquisite sensitivity to EZH2 inhibition in both adherent and tumorsphere conditions, due in part to derepression of neurogenesis genes, including REST targets. Examination of the epigenomic landscape of a pediatric neuroblastoma ... (Show More)

Study Datasets 2 datasets.

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Dataset ID Description Technology Samples
WGS and WXS files for Dyer ATRX study
Illumina HiSeq 2000 6
ATRX SNP6 data on Affymetrix 600k
Affymetrix 600K N/A

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