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.

中文翻译：

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ATRX 框内融合神经母细胞瘤通过调节神经元基因特征对 EZH2 抑制敏感。

ATRX 改变在青少年和年轻人的神经母细胞瘤中发生频率很高。特别有趣的是 ATRX（阿尔法地中海贫血/精神发育迟滞，X 连锁）的 N 端大缺失，产生缺乏关键染色质相互作用域的框内融合 (IFF) 蛋白，同时保留了 SWI/SNF 样解旋酶区域。我们证明 ATRX IFF 蛋白从富含 H3K9me3 的染色质重新分配到活性基因的启动子，并将 REST 识别为 ATRX IFF 目标，其激活促进神经元分化基因的沉默。我们进一步表明 ATRX IFF 细胞对 EZH2 抑制剂表现出敏感性，这是由于神经发生基因的抑制，包括 REST 靶标的一个子集。综合起来，