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. (April 2010) Genome-wide RNA-mediated interference screen identifies miR-19 targets in Notch-induced T-cell acute lymphoblastic leukaemia. Nature Cell Biology, 12 (4). 372-U159. ISSN 1465-7392
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.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | ACTIVATING MUTATIONS MICRORNAS EXPRESSION AUTOIMMUNITY LYMPHOCYTES NEOPLASMS LYMPHOMAS SURVIVAL MAMMALS DISEASE |
| Subjects: | diseases & disorders > cancer diseases & disorders > cancer > cancer types > leukemia bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > miRNA bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > miRNA bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations |
| CSHL Authors: | |
| Communities: | CSHL labs > Lowe lab School of Biological Sciences > Publications |
| Depositing User: | CSHL Librarian |
| Date: | April 2010 |
| Date Deposited: | 03 Oct 2011 16:08 |
| Last Modified: | 22 Sep 2014 19:28 |
| PMCID: | PMC2989719 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/15477 |
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