Genetic dissection of the miR-17∼92 cluster of microRNAs in Myc-induced B-cell lymphomas
Genetic dissection of the miR-17∼92 cluster of microRNAs in Myc-induced B-cell lymphomas
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DOI：
10.1101/gad.1872909
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发表时间：
2009-12-15
影响因子：
10.5
通讯作者：
Ventura, Andrea
中科院分区：
文献类型：
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作者：
Mu, Ping;Han, Yoon-Chi;Ventura, Andrea
类似于92簇的miR-17在人类癌症中经常被扩增或过表达，并已成为典型的致癌多顺子microRNA （miRNA）。类似于92的miR-17是c-Myc的直接转录靶点，在b细胞淋巴瘤小鼠模型中的实验显示这两个癌基因之间存在合作关系。然而，这种合作的分子机制和负责这种合作的单个mirna都是未知的。通过使用类似于92的miR-17的条件敲除等位基因，我们在这里表明，在myc驱动的b细胞淋巴瘤中，需要持续表达类似于92的内源性miR-17来抑制细胞凋亡。此外，我们发现在类似于92的6个由miR-17编码的mirna中，miR-19a和miR-19b是绝对必需的，并且在很大程度上足以概括整个簇的致癌特性。最后，通过结合计算靶点预测、基因表达谱和体外筛选策略，我们确定了介导其促生存活性的miR-19靶点子集。
The miR-17 similar to 92 cluster is frequently amplified or over-expressed in human cancers and has emerged as the prototypical oncogenic polycistron microRNA (miRNA). miR-17 similar to 92 is a direct transcriptional target of c-Myc, and experiments in a mouse model of B-cell lymphomas have shown cooperation between these two oncogenes. However, both the molecular mechanism underlying this cooperation and the individual miRNAs that are responsible for it are unknown. By using a conditional knockout allele of miR-17 similar to 92, we show here that sustained expression of endogenous miR-17 similar to 92 is required to suppress apoptosis in Myc-driven B-cell lymphomas. Furthermore, we show that among the six miRNAs that are encoded by miR-17 similar to 92, miR-19a and miR-19b are absolutely required and largely sufficient to recapitulate the oncogenic properties of the entire cluster. Finally, by combining computational target prediction, gene expression profiling, and an in vitro screening strategy, we identify a subset of miR-19 targets that mediate its pro-survival activity.