Genome-wide RNA-mediated interference screen identifies miR-19 targets in Notch-induced T-cell acute lymphoblastic leukaemia

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

URL: http://www.ncbi.nlm.nih.gov/pubmed/20190740
DOI: 10.1038/ncb2037

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
Watson School > 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: http://repository.cshl.edu/id/eprint/15477

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