Cancer Biology & Genetics Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
Nat Cell Biol. 2010 Apr;12(4):372-9. doi: 10.1038/ncb2037. Epub 2010 Feb 28.
MicroRNAs (miRNAs) have emerged as novel cancer genes. In particular, the miR-17-92 cluster, containing six individual miRNAs, is highly expressed in haematopoietic cancers and promotes lymphomagenesis in vivo. Clinical use of these findings hinges on isolating the oncogenic activity within the 17-92 cluster and defining its relevant target genes. Here we show that miR-19 is sufficient to promote leukaemogenesis in Notch1-induced T-cell acute lymphoblastic leukaemia (T-ALL) in vivo. In concord with the pathogenic importance of this interaction in T-ALL, we report a novel translocation that targets the 17-92 cluster and coincides with a second rearrangement that activates Notch1. To identify the miR-19 targets responsible for its oncogenic action, we conducted a large-scale short hairpin RNA screen for genes whose knockdown can phenocopy miR-19. Strikingly, the results of this screen were enriched for miR-19 target genes, and include Bim (Bcl2L11), AMP-activated kinase (Prkaa1) and the phosphatases Pten and PP2A (Ppp2r5e). Hence, an unbiased, functional genomics approach reveals a coordinate clampdown on several regulators of phosphatidylinositol-3-OH kinase-related survival signals by the leukaemogenic miR-19.
微小 RNA（miRNA）已成为新的癌症基因。特别是，包含六个单独 miRNA 的 miR-17-92 簇在造血系统癌症中高度表达，并在体内促进淋巴瘤发生。这些发现的临床应用取决于分离 17-92 簇中的致癌活性并定义其相关靶基因。在这里，我们表明 miR-19 足以在 Notch1 诱导的 T 细胞急性淋巴细胞白血病（T-ALL）中促进白血病发生。与这种相互作用在 T-ALL 中的发病重要性一致，我们报告了一种新的易位，该易位靶向 17-92 簇，并与激活 Notch1 的第二个重排同时发生。为了确定负责其致癌作用的 miR-19 靶基因，我们进行了大规模短发夹 RNA 筛选，以寻找可模拟 miR-19 的基因敲低。引人注目的是，该筛选的结果富含 miR-19 靶基因，包括 Bim（Bcl2L11）、AMP 激活的激酶（Prkaa1）和磷酸酶 Pten 和 PP2A（Ppp2r5e）。因此，一种无偏见的、功能基因组学方法揭示了白血病致癌 miR-19 通过协调机制抑制几种与磷酸肌醇 3-OH 激酶相关的存活信号调节剂。
