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

Publication date: Available online 17 October 2019Source: Cancer CellAuthor(s): 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 GallegoSummaryATRX 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.Graphical Abstract
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research