A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia.
A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia.
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DOI：
10.1016/j.celrep.2016.09.079
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发表时间：
2016-10-18
期刊：
影响因子：
8.8
通讯作者：
Yusa K
中科院分区：
文献类型：
--
作者：
Tzelepis K;Koike-Yusa H;De Braekeleer E;Li Y;Metzakopian E;Dovey OM;Mupo A;Grinkevich V;Li M;Mazan M;Gozdecka M;Ohnishi S;Cooper J;Patel M;McKerrell T;Chen B;Domingues AF;Gallipoli P;Teichmann S;Ponstingl H;McDermott U;Saez-Rodriguez J;Huntly BJP;Iorio F;Pina C;Vassiliou GS;Yusa K
急性髓系白血病(AML)是一种侵袭性强、预后差的癌症，其主流治疗方法几十年来一直没有改变。为了确定AML的其他治疗靶点，我们优化了全基因组集群规则间隔短回文重复(CRISPR)筛查平台，并使用它来识别AML细胞中的遗传脆弱性。我们确定了492个AML特异性细胞必需基因，包括几个已建立的治疗靶点，如DOT1L、BCL2和MEN1，以及许多其他基因，包括临床上可操作的候选基因。我们使用遗传和药物抑制来验证选定的基因，并选择KAT2A作为下游研究的候选基因。KAT2A抑制通过诱导髓系分化和凋亡显示了抗AML活性，并抑制了不同基因型人原代AML的生长，而保留了正常的造血干/祖细胞。我们的结果建议，应该研究抑制KAT2A作为AML的一种治疗策略，并提供这种白血病的大量遗传易感性，可以在后续研究中继续研究。用于鉴定全基因组遗传脆弱性的优化CRISPR平台急性髓系白血病细胞系遗传脆弱性目录KAT2A抑制诱导髓系分化和凋亡KAT2A抑制抑制原代AML细胞的生长，但不阻止正常祖细胞Tzelepis等人的生长。优化基于CRISPR-Cas9的全基因组隐性筛选平台，并将其应用于识别人类AML细胞的遗传脆弱性。他们确定了几个已知的治疗靶点，包括BRD4、DOT1L和MEN1，以及许多其他候选药物。他们提供的数据表明KAT2A是一个潜在的治疗靶点。
Acute myeloid leukemia (AML) is an aggressive cancer with a poor prognosis, for which mainstream treatments have not changed for decades. To identify additional therapeutic targets in AML, we optimize a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening platform and use it to identify genetic vulnerabilities in AML cells. We identify 492 AML-specific cell-essential genes, including several established therapeutic targets such as DOT1L, BCL2, and MEN1, and many other genes including clinically actionable candidates. We validate selected genes using genetic and pharmacological inhibition, and chose KAT2A as a candidate for downstream study. KAT2A inhibition demonstrated anti-AML activity by inducing myeloid differentiation and apoptosis, and suppressed the growth of primary human AMLs of diverse genotypes while sparing normal hemopoietic stem-progenitor cells. Our results propose that KAT2A inhibition should be investigated as a therapeutic strategy in AML and provide a large number of genetic vulnerabilities of this leukemia that can be pursued in downstream studies. Optimized CRISPR platform for identification of genome-wide genetic vulnerabilities Catalog of genetic vulnerabilities in acute myeloid leukemia cell lines KAT2A inhibition induces myeloid differentiation and apoptosis KAT2A inhibition arrests the growth of primary AML cells, but not of normal progenitors Tzelepis et al. optimize a CRISPR-Cas9-based platform for the performance of genome-wide recessive screens and apply it to identify genetic vulnerabilities of human AML cells. They identify several known therapeutic targets including BRD4, DOT1L, and MEN1, and numerous additional candidates. They provide data proposing KAT2A as a potential therapeutic target.
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影响因子：
64.8
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影响因子：
64.8
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影响因子：
12.3
作者：
Dang Y;Jia G;Choi J;Ma H;Anaya E;Ye C;Shankar P;Wu H
通讯作者：
Wu H
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作者：
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通讯作者：
Root DE
影响因子：
56.9
作者：
Jinek, Martin;Chylinski, Krzysztof;Charpentier, Emmanuelle
通讯作者：
Charpentier, Emmanuelle