期刊
NATURE CELL BIOLOGY
卷 12, 期 4, 页码 372-U159出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb2037
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资金
- American Cancer Society
- Geoffrey Beene Cancer Center
- Leukemia Research Foundation
- Louis V. Gerstner Foundation
- May and Samuel Rudin Foundation
- NY Community Trust
- William and Blanche Foundation
- Andrew Seligson Memorial Clinical Fellowship
- NYStar
- WOLF Foundation
- Rally across America Foundation
- Leukemia and Lymphoma Society [1287-08, 6237-08]
- [R01CA120196]
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.
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