Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS.
Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS.
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DOI：
10.1016/j.ccell.2018.01.012
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发表时间：
2018-03-12
期刊：
影响因子：
50.3
通讯作者：
Maeda T
中科院分区：
文献类型：
--
作者：
Yamauchi T;Masuda T;Canver MC;Seiler M;Semba Y;Shboul M;Al-Raqad M;Maeda M;Schoonenberg VAC;Cole MA;Macias-Trevino C;Ishikawa Y;Yao Q;Nakano M;Arai F;Orkin SH;Reversade B;Buonamici S;Pinello L;Akashi K;Bauer DE;Maeda T
为了确定急性髓性白血病（AML）治疗的新靶点，我们使用AML细胞系进行了全基因组CRISPR-Cas9筛选，然后进行了体内第二次筛选。在这里，我们表明，mRNA脱帽酶清除剂（DCPS）基因是AML细胞生存所必需的。如质谱所示，DCPS酶与前mRNA代谢途径的组分相互作用，包括剪接体。RG 3039是一种最初开发用于治疗脊髓性肌萎缩症的DCPS抑制剂，通过诱导前体mRNA错误剪接表现出抗白血病活性。携带生殖系双等位基因DCPS功能丧失突变的人不表现出异常的血液学表型，表明DCPS对人类造血作用不利。我们的研究结果揭示了前mRNA代谢途径，并确定DCPS作为AML治疗的靶点。Yamauchi等人对p53 WT AML进行了体外和体内CRISPR-Cas9遗传筛选，以鉴定潜在的治疗靶点。他们发现AML依赖于DCPS脱帽酶，DCPS抑制剂在肿瘤模型中显示出抗白血病活性，而不影响正常的造血。
To identify novel targets for acute myeloid leukemia (AML) therapy, we performed genome-wide CRISPR-Cas9 screening using AML cell lines, followed by a second screen in vivo. Here, we show that the mRNA decapping enzyme scavenger (DCPS) gene is essential for AML cell survival. The DCPS enzyme interacted with components of pre-mRNA metabolic pathways, including spliceosomes, as revealed by mass spectrometry. RG3039, a DCPS inhibitor originally developed to treat spinal muscular atrophy, exhibited anti-leukemic activity via inducing pre-mRNA mis-splicing. Humans harboring germline bi-allelic DCPS loss-of-function mutations do not exhibit aberrant hematologic phenotypes, indicating that DCPS is dispensable for human hematopoiesis. Our findings shed light on a pre-mRNA metabolic pathway and identify DCPS as a target for AML therapy. Yamauchi et al. perform in vitro and in vivo CRISPR-Cas9 genetic screening of p53 WT AML to identify potential therapeutic targets. They find that AML relies on the DCPS decapping enzyme, and a DCPS inhibitor shows anti-leukemia activity in tumor models without impacting normal hematopoiesis.
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影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
Biopython：用于计算分子生物学和生物信息学的免费 Python 工具。
DOI：
10.1093/bioinformatics/btp163
发表时间：
2009-06-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Cock PJ;Antao T;Chang JT;Chapman BA;Cox CJ;Dalke A;Friedberg I;Hamelryck T;Kauff F;Wilczynski B;de Hoon MJ
通讯作者：
de Hoon MJ
影响因子：
16
作者：
Gu, MG;Fabrega, C;Lima, CD
通讯作者：
Lima, CD
影响因子：
56.9
作者：
Jinek, Martin;Chylinski, Krzysztof;Charpentier, Emmanuelle
通讯作者：
Charpentier, Emmanuelle
影响因子：
46.9
作者：
Cho, Seung Woo;Kim, Sojung;Kim, Jin-Soo
通讯作者：
Kim, Jin-Soo