RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia.
RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia.
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DOI：
10.1038/nature10334
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发表时间：
2011-08-03
期刊：
影响因子：
64.8
通讯作者：
Vakoc, Christopher R.
中科院分区：
文献类型：
--
作者：
Zuber, Johannes;Shi, Junwei;Wang, Eric;Rappaport, Amy R.;Herrmann, Harald;Sison, Edward A.;Magoon, Daniel;Qi, Jun;Blatt, Katharina;Wunderlich, Mark;Taylor, Meredith J.;Johns, Christopher;Chicas, Agustin;Mulloy, James C.;Kogan, Scott C.;Brown, Patrick;Valent, Peter;Bradner, James E.;Lowe, Scott W.;Vakoc, Christopher R.
表观遗传途径可以通过控制和解释染色质修饰来调节基因表达。癌细胞的特点是表观遗传景观发生改变，并且通常利用染色质调节机制来执行致癌基因表达程序。尽管染色质改变原则上是可逆的，并且通常易于药物干预，但由于对表观遗传调节因子的癌症特异性依赖性的不完全了解，在治疗上靶向此类途径的前景受到限制。在这里，我们描述了一种无偏见的方法来探测急性髓系白血病（AML）的表观遗传脆弱性，这是一种侵袭性造血恶性肿瘤，通常与异常染色质状态相关。通过在基因定义的 AML 小鼠模型中筛选针对已知染色质调节因子的定制小发夹 RNA (shRNA) 文库，我们确定了含溴结构域 4 (Brd4) 的蛋白是疾病维持所必需的。使用 shRNA 或小分子抑制剂 JQ1 抑制 Brd4 可在体外和体内产生强大的抗白血病作用，并伴有终末骨髓分化和白血病干细胞的消除。在多种人类 AML 细胞系和原发性患者样本中观察到类似的敏感性，表明 JQ1 在不同的 AML 亚型中具有广泛的活性。 Brd4 抑制的作用至少部分归因于其在维持 Myc 表达以促进异常自我更新方面的作用，这表明 JQ1 作为抑制癌症中 MYC 的药理学手段。我们的结果确立了 Brd4 的小分子抑制作为 AML 和其他癌症的一种有前途的治疗策略，并强调了 RNA 干扰 (RNAi) 筛选在揭示表观遗传脆弱性方面的效用，这些脆弱性可用于直接药理干预。
Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention.
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影响因子：
64.5
作者：
Kim J;Woo AJ;Chu J;Snow JW;Fujiwara Y;Kim CG;Cantor AB;Orkin SH
通讯作者：
Orkin SH
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
20.3
作者：
Vardiman, James W.;Thiele, Juergen;Bloomfield, Clara D.
通讯作者：
Bloomfield, Clara D.
影响因子：
23.9
作者：
Somervaille TC;Matheny CJ;Spencer GJ;Iwasaki M;Rinn JL;Witten DM;Chang HY;Shurtleff SA;Downing JR;Cleary ML
通讯作者：
Cleary ML
影响因子：
64.8
作者：
Soucek, Laura;Whitfield, Jonathan;Martins, Carla P.;Finch, Andrew J.;Murphy, Daniel J.;Sodir, Nicole M.;Karnezis, Anthony N.;Swigart, Lamorna Brown;Nasi, Sergio;Evan, Gerard I.
通讯作者：
Evan, Gerard I.