Transcription control by the ENL YEATS domain in acute leukaemia.
Transcription control by the ENL YEATS domain in acute leukaemia.
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DOI：
10.1038/nature21688
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发表时间：
2017-03-09
期刊：
影响因子：
64.8
通讯作者：
Bradner JE
中科院分区：
文献类型：
--
作者：
Erb MA;Scott TG;Li BE;Xie H;Paulk J;Seo HS;Souza A;Roberts JM;Dastjerdi S;Buckley DL;Sanjana NE;Shalem O;Nabet B;Zeid R;Offei-Addo NK;Dhe-Paganon S;Zhang F;Orkin SH;Winter GE;Bradner JE
涉及混合谱系白血病基因（MLL）的复发性染色体易位引起高度侵袭性的急性白血病，与不良临床结局相关。染色质相关因子优先参与MLL重排掩盖了对转录控制的依赖性。尽管最近在靶向癌症中的染色质调节剂方面取得了进展，但针对这种特征明确的疾病的可用疗法仍然不足，促使目前努力使新靶点有资格用于治疗干预。使用无偏见的新兴CRISPR-Cas9技术在MLL-AF 4阳性急性白血病中进行基因组规模的功能丧失筛选，我们将ENL（11 - 19白血病）鉴定为一种未被识别的依赖性，对于体外和体内增殖特别重要。为了解释ENL在白血病发病机制和动态转录控制中的机制作用，我们采用了一种利用靶向蛋白降解的化学遗传策略。急性ENL丢失抑制转录起始和延伸全基因组，在基因具有显着的效果不成比例的ENL负荷。重要的是，ENL依赖性白血病生长取决于完整的YEATS染色质阅读器结构域。这些发现揭示了急性白血病中的一种新的依赖性，以及破坏疾病中YEATS结构域的第一个机械理性。
Recurrent chromosomal translocations involving the mixed lineage leukemia gene (MLL) give rise to a highly aggressive acute leukemia associated with poor clinical outcome. The preferential involvement of chromatin-associated factors in MLL rearrangement 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 present effort to qualify new targets for therapeutic intervention. Using unbiased, emerging CRISPR-Cas9 technology to perform a genome-scale loss-of-function screen in MLL-AF4-positive acute leukemia, we identified ENL (eleven-nineteen leukemia) as an unrecognized dependency particularly indispensable for proliferation in vitro and in vivo. To explain the mechanistic role for ENL in leukemia pathogenesis and dynamic transcription control, we pursued a chemical genetic strategy utilizing targeted protein degradation. Acute ENL loss suppresses transcription initiation and elongation genome-wide, with pronounced effects at genes featuring disproportionate ENL load. Importantly, ENL-dependent leukemic growth was contingent upon an intact YEATS chromatin reader domain. These findings reveal a novel dependency in acute leukemia and a first mechanistic rational for disrupting the YEATS domain in disease.