Genome-wide RNAi screen identifies miR-19 targets in Notch-induced acute T-cell leukaemia (T-ALL)

MicroRNAs (miRNAs) have emerged as novel cancer genes. In particular, the 17~92 cluster of miRNAs is highly expressed in haematopoietic cancers and promotes lymphomagenesis in vivo1,2. 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 lymphoblastic leukaemia (T-ALL) in vivo. Consistent with the pathogenic importance of this interaction, we report a novel translocation targeting the 17~92 miRNA cluster coinciding with a second rearrangement that activates Notch1 in T-ALL. To identify the miR-19 targets responsible for its oncogenic action, we conducted a large-scale short-hairpin RNA (shRNA) screen for genes whose knockdown could phenocopy miR-19. Strikingly, the results of this screen were enriched for miR-19 target genes, and included Bim (Bcl2L11)1,3, AMP-activated kinase (Prkaa1), and the tumour suppressor phosphatases Pten and PP2A (Ppp2r5e). Hence, an unbiased, functional genomics approach reveals a coordinate clamp down on several regulators of PI3K-related survival signals by the leukaemogenic miR-19.

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Mavrakis KJ, Wolfe AL, Oricchio E, Palomero T, de Keersmaecker K, McJunkin K, Zuber J, James T, Khan AA, Leslie CS, Parker JS, Paddison PJ, Tam W, Ferrando A, Wendel HG