ATRX In-Frame Fusion Neuroblastoma Is Sensitive to EZH2 Inhibition via Modulation of Neuronal Gene Signatures.

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.

• Authors: Zulekha A Qadeer, David Valle-Garcia, Dan Hasson, Zhen Sun, April Cook, Christie Nguyen, Aroa Soriano, Anqi Ma, Lyra M Griffiths, Maged Zeineldin, Dan Filipescu, Luz Jubierre, Asif Chowdhury, Orla Deevy, Xiang Chen, David B Finkelstein, Armita Bahrami, Elizabeth Stewart, Sara Federico, Soledad Gallego, Fumiko Dekio, Mary Fowkes, David Meni, John M Maris, William A Weiss, Stephen S Roberts, Nai-Kong V Cheung, Jian Jin, Miguel F Segura, Michael A Dyer, Emily Bernstein
• Journal: Cancer cell (Cancer Cell) Vol. 36 Issue 5 Pg. 512-527.e9 (11 11 2019) ISSN: 1878-3686 [Electronic] United States
• PMID: 31631027 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Chromatin
• Histones
• RE1-silencing transcription factor
• Repressor Proteins
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein
• ATRX protein, human
• X-linked Nuclear Protein

Topics

• Animals
• Base Sequence (genetics)
• Cell Differentiation (genetics)
• Cell Line, Tumor
• Chromatin (metabolism)
• Enhancer of Zeste Homolog 2 Protein (antagonists & inhibitors, metabolism)
• Epigenesis, Genetic
• Female
• Gene Expression Regulation, Neoplastic
• Histones (metabolism)
• Humans
• Male
• Mice
• Neuroblastoma (drug therapy, genetics, pathology, surgery)
• Neurogenesis (drug effects, genetics)
• Neurons (drug effects, metabolism, pathology)
• Promoter Regions, Genetic
• Protein Domains (genetics)
• Repressor Proteins (genetics)
• Sequence Deletion
• X-linked Nuclear Protein (genetics, metabolism)
• Xenograft Model Antitumor Assays