Genome-wide RNA-mediated interference screen identifies miR-19 targets in Notch-induced T-cell acute lymphoblastic leukaemia Journal Article
| Authors: | Mavrakis, K. J.; Wolfe, A. L.; Oricchio, E.; Palomero, T.; De Keersmaecker, K.; McJunkin, K.; Zuber, J.; James, T.; Chang, K.; Khan, A. A.; Leslie, C. S.; Parker, J. S.; Paddison, P. J.; Tam, W.; Ferrando, A.; Wendel, H. G. |
| Article Title: | Genome-wide RNA-mediated interference screen identifies miR-19 targets in Notch-induced T-cell acute lymphoblastic leukaemia |
| Abstract: | 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. © 2010 Macmillan Publishers Limited. All rights reserved. |
| Keywords: | signal transduction; controlled study; gene cluster; nonhuman; cell proliferation; animal cell; mouse; animals; mice; cell survival; gene targeting; microrna; bim protein; genome-wide association study; rna interference; receptor, notch1; cell line, tumor; acute lymphoblastic leukemia; time factors; transduction, genetic; cell transformation, neoplastic; oncogenes; gene activation; gene rearrangement; gene interaction; nucleotide sequence; leukemogenesis; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; 1-phosphatidylinositol 3-kinase; translocation, genetic; micrornas; genetic screening; t cell leukemia; short hairpin rna; gene knockdown techniques; notch1 receptor; gene activity; gene expression regulation, leukemic; precursor t-cell lymphoblastic leukemia-lymphoma; gene rearrangement, t-lymphocyte; protein rna binding; hydroxymethylglutaryl coenzyme a reductase kinase |
| Journal Title: | Nature Cell Biology |
| Volume: | 12 |
| Issue: | 4 |
| ISSN: | 1465-7392 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2010-04-01 |
| Start Page: | 372 |
| End Page: | 379 |
| Language: | English |
| DOI: | 10.1038/ncb2037 |
| PUBMED: | 20190740 |
| PROVIDER: | scopus |
| PMCID: | PMC2989719 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 15" - "Export Date: 20 April 2011" - "CODEN: NCBIF" - "Source: Scopus" |
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