白血病转录调控核心元素:ENL蛋白
  • 复发性染色体转位,产生嵌合型MLL癌基因,引起高度侵袭性急性白血病,临床预后差,染色质相关因子如MLL融合伴侣的参与,掩盖转录调控依赖;
  • 采用无偏CRISPR-Cas9技术,在MLL-AF4阳性急性白血病细胞株中进行全基因组功能缺失筛选,鉴定出ENL新基因,增殖所必需;
  • ENL急性缺失抑制全基因组范围内效应基因的RNA聚合酶II的启动和延伸,对ENL负荷失衡的基因产生持续影响;
  • YEATS染色质阅读结构域不完整,是ENL依赖性白血病生长的必需条件。
关键字
延伸阅读本研究的原文信息和链接出处,以及相关解读和评论文章。欢迎读者朋友们推荐!
图片
Nature [IF:42.778]

Transcription control by the ENL YEATS domain in acute leukaemia

急性白血病中ENL YEATS结构域的转录调控

10.1038/nature21688

2017-03-01, Letter

Abstract & Authors:展开

Abstract:收起
Recurrent chromosomal translocations producing a chimaeric MLL oncogene give rise to a highly aggressive acute leukaemia associated with poor clinical outcome. The preferential involvement of chromatin-associated factors as MLL fusion partners belies a dependency on transcription control. Despite recent progress made in targeting chromatin regulators in cancer, available therapies for this well-characterized disease remain inadequate, prompting the need to identify new targets for therapeutic intervention. Here, using unbiased CRISPR-Cas9 technology to perform a genome-scale loss-of-function screen in an MLL-AF4-positive acute leukaemia cell line, we identify ENL as an unrecognized gene that is specifically required for proliferation in vitro and in vivo. To explain the mechanistic role of ENL in leukaemia pathogenesis and dynamic transcription control, a chemical genetic strategy was developed to achieve targeted protein degradation. Acute loss of ENL suppressed the initiation and elongation of RNA polymerase II at active genes genome-wide, with pronounced effects at genes featuring a disproportionate ENL load. Notably, an intact YEATS chromatin-reader domain was essential for ENL-dependent leukaemic growth. Overall, these findings identify a dependency factor in acute leukaemia and suggest a mechanistic rationale for disrupting the YEATS domain in disease.

First Authors:
Michael A Erb

Correspondence Authors:
James E Bradner

All Authors:
Michael A Erb,Thomas G Scott,Bin E Li,Huafeng Xie,Joshiawa Paulk,Hyuk-Soo Seo,Amanda Souza,Justin M Roberts,Shiva Dastjerdi,Dennis L Buckley,Neville E Sanjana,Ophir Shalem,Behnam Nabet,Rhamy Zeid,Nana K Offei-Addo,Sirano Dhe-Paganon,Feng Zhang,Stuart H Orkin,Georg E Winter,James E Bradner

评论