Genetic dissection of the miR-17∼92 cluster of microRNAs in Myc-induced B-cell lymphomas
- Ping Mu1,5,
- Yoon-Chi Han1,5,
- Doron Betel2,
- Evelyn Yao1,
- Massimo Squatrito1,
- Paul Ogrodowski1,
- Elisa de Stanchina3,
- Aleco D'Andrea1,4,
- Chris Sander2 and
- Andrea Ventura1,6
- 1Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA;
- 2Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA;
- 3Department of Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA;
- 4Department of Surgical and Oncological Sciences, Section of Medical Oncology, Università di Palermo, Palermo 90133, Italy
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↵5 These authors contributed equally to this work.
Abstract
The miR-17∼92 cluster is frequently amplified or overexpressed in human cancers and has emerged as the prototypical oncogenic polycistron microRNA (miRNA). miR-17∼92 is a direct transcriptional target of c-Myc, and experiments in a mouse model of B-cell lymphomas have shown cooperation between these two oncogenes. However, both the molecular mechanism underlying this cooperation and the individual miRNAs that are responsible for it are unknown. By using a conditional knockout allele of miR-17∼92, we show here that sustained expression of endogenous miR-17∼92 is required to suppress apoptosis in Myc-driven B-cell lymphomas. Furthermore, we show that among the six miRNAs that are encoded by miR-17∼92, miR-19a and miR-19b are absolutely required and largely sufficient to recapitulate the oncogenic properties of the entire cluster. Finally, by combining computational target prediction, gene expression profiling, and an in vitro screening strategy, we identify a subset of miR-19 targets that mediate its prosurvival activity.
Keywords
Footnotes
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↵6 Corresponding author.
E-MAIL venturaa{at}mskcc.org; FAX (646) 422-0871.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1872909.
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Supplemental material is available at http://www.genesdev.org.
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- Received October 11, 2009.
- Accepted November 3, 2009.
- Copyright © 2009 by Cold Spring Harbor Laboratory Press
