title: Genetic dissection of the miR-17~92 cluster of microRNAs in Myc-induced B-cell lymphomas.
abstract: The miR-17 approximately 92 cluster is frequently amplified or overexpressed in human cancers and has emerged as the prototypical oncogenic polycistron microRNA (miRNA). miR-17 approximately 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 approximately 92, we show here that sustained expression of endogenous miR-17 approximately 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 approximately 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.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Mu
authors.forename: Yoon-Chi
authors.initials: YC
authors.lastname: Han
authors.forename: Doron
authors.initials: D
authors.lastname: Betel
authors.forename: Evelyn
authors.initials: E
authors.lastname: Yao
authors.forename: Massimo
authors.initials: M
authors.lastname: Squatrito
authors.forename: Paul
authors.initials: P
authors.lastname: Ogrodowski
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.forename: Aleco
authors.initials: A
authors.lastname: D'Andrea
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.forename: Andrea
authors.initials: A
authors.lastname: Ventura
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D017353:Gene Deletion; D016259:Genes, myc / Q000235:genetics*; D016393:Lymphoma, B-Cell / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism
chemical_list: D035683:MicroRNAs