当前位置:科学网首页 > 小柯机器人 >详情
ATRX基因突变神经母细胞瘤亚型对EZH2抑制剂敏感
作者:小柯机器人 发布时间:2019/10/18 15:56:50

美国西奈山伊坎医学院Emily Bernstein研究团队发现,ATRX基因框内融合突变的神经母细胞瘤对EZH2的抑制敏感,这是通过调节神经元特征基因来实现的。相关论文于2019年10月17日在线发表在《癌细胞》杂志上。

研究人员发现ATRX阅读框内融合(IFF)蛋白从富含H3K9me3的染色质重新分布到活跃基因的启动子,并将REST基因鉴定为ATRX IFF目标,其激活促进了神经元分化基因的沉默。 研究人员进一步表明,由于神经生成基因(包括REST靶基因中的一部分)的抑制,ATRX IFF细胞显示出对EZH2抑制剂的敏感性。因此,研究人员证明了ATRX结构的改变不是功能丧失,并提出了EZH2抑制剂作为ATRX IFF神经母细胞瘤的潜在疗法。

据介绍,ATRX基因改变在青少年和年轻人的神经母细胞瘤中频繁发生。特别令人感兴趣的是ATRX(全称为Alpha Thalassemia/Mental Retardation,与X染色体连锁)的N末端大片段缺失,可产生无关键染色质相互作用域的IFF蛋白,同时保留SWI/SNF样解旋酶区域。

附:英文原文

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

Author: 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

Issue&Volume: 17 October 2019

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.

DOI: 10.1016/j.ccell.2019.09.002

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30385-X

期刊信息

Cancer Cell:《癌细胞》,创刊于2002年。隶属于细胞出版社,最新IF:23.916
官方网址:https://www.cell.com/cancer-cell/home
投稿链接:https://www.editorialmanager.com/cancer-cell/default.aspx