| Literature DB >> 31631027 |
Zulekha A Qadeer1, David Valle-Garcia2, Dan Hasson2, Zhen Sun3, April Cook2, Christie Nguyen3, Aroa Soriano4, Anqi Ma5, Lyra M Griffiths6, Maged Zeineldin6, Dan Filipescu2, Luz Jubierre4, Asif Chowdhury2, Orla Deevy2, Xiang Chen7, David B Finkelstein7, Armita Bahrami8, Elizabeth Stewart9, Sara Federico10, Soledad Gallego11, Fumiko Dekio12, Mary Fowkes12, David Meni13, John M Maris14, William A Weiss15, Stephen S Roberts13, Nai-Kong V Cheung13, Jian Jin16, Miguel F Segura4, Michael A Dyer6, Emily Bernstein17.
Abstract
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.Entities:
Keywords: ATRX; EZH2; REST; epigenetic therapeutics; neuroblastoma; neuronal differentiation; tazemetostat
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Year: 2019 PMID： 31631027 PMCID： PMC6851493 DOI： 10.1016/j.ccell.2019.09.002
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 38.585