ATRX In-Frame Fusion Neuroblastoma Is Sensitive to EZH2 Inhibition via Modulation of Neuronal Gene Signatures.
ATRX alterations occur at high frequency in neuroblastoma of adolescents and young adults. Particularly intriguing are the large N-terminal deletions of ATRX (Alpha Thalassemia/Mental Retardation, X-linked) that generate in-frame fusion (IFF) proteins devoid of key chromatin interaction domains, while retaining the SWI/SNF-like helicase region. We demonstrate that ATRX IFF proteins ... are redistributed from H3K9me3-enriched chromatin to promoters of active genes and identify REST as an ATRX IFF target whose activation promotes silencing of neuronal differentiation genes. We further show that ATRX IFF cells display sensitivity to EZH2 inhibitors, due to derepression of neurogenesis genes, including a subset of REST targets. Taken together, we demonstrate that ATRX structural alterations are not loss-of-function and put forward EZH2 inhibitors as a potential therapy for ATRX IFF neuroblastoma.
Mesh Terms:
Animals, Base Sequence, Cell Differentiation, Cell Line, Tumor, Chromatin, Enhancer of Zeste Homolog 2 Protein, Epigenesis, Genetic, Female, Gene Expression Regulation, Neoplastic, Histones, Humans, Male, Mice, Neuroblastoma, Neurogenesis, Neurons, Promoter Regions, Genetic, Protein Domains, Repressor Proteins, Sequence Deletion, X-linked Nuclear Protein, Xenograft Model Antitumor Assays
Animals, Base Sequence, Cell Differentiation, Cell Line, Tumor, Chromatin, Enhancer of Zeste Homolog 2 Protein, Epigenesis, Genetic, Female, Gene Expression Regulation, Neoplastic, Histones, Humans, Male, Mice, Neuroblastoma, Neurogenesis, Neurons, Promoter Regions, Genetic, Protein Domains, Repressor Proteins, Sequence Deletion, X-linked Nuclear Protein, Xenograft Model Antitumor Assays
Cancer Cell
Date: Dec. 11, 2018
PubMed ID: 31631027
View in: Pubmed Google Scholar
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