To date, more than 200 microRNAs have been described in humans; however, the precise functions of these regulatory, non-coding RNAs remains largely obscure. One cluster of microRNAs, the mir-17-92 polycistron, is located in a region of DNA that is amplified in human B-cell lymphomas 1 . Here we compared B-cell lymphoma samples and cell lines to normal tissues, and found that the levels of the primary or mature microRNAs derived from the mir-17-92 locus are often substantially increased in these cancers. Enforced expression of the mir-17-92 cluster acted with c-myc expression to accelerate tumour development in a mouse B-cell lymphoma model. Tumours derived from haematopoietic stem cells expressing a subset of the mir-17-92 cluster and c-myc could be distinguished by an absence of apoptosis that was otherwise prevalent in c-myc-induced lymphomas. Together, these studies indicate that non-coding RNAs, specifically microRNAs, can modulate tumour formation, and implicate the mir-17-92 cluster as a potential human oncogene.MicroRNAs (miRNAs) have emerged relatively recently as a new class of small, non-coding RNAs that regulate gene expression. Nascent primary miRNA transcripts (pri-miRNAs) are processed sequentially by two RNase III enzymes, Drosha and Dicer 2,3 , to yield mature miRNAs, ranging from 18 to 24 nucleotides (nt) in length. miRNAs are incorporated into the RNA interference (RNAi) effector complex, RISC, and target specific messenger RNAs Reprints and permissions information is available at npg.nature.com/reprintsandpermissionsCorrespondence and requests for materials should be addressed to G.J.H. (hannon@cshl.edu) or S.M.H. (hammond@med.unc.edu). * These authors contributed equally to this work.Supplementary Information is linked to the online version of the paper at www.nature.com/nature.Microarray data have been deposited in NCBI-GEO under accession numbers GSM45026-GSM45065 and GSE-2399.The authors declare no competing financial interests. -6 and miR-273 (refs 9, 10). Bantam stimulates cell growth and prevents apoptosis in Drosophila 11 , and miR-181 potentiates B-cell differentiation in mammals 12 . These findings, in combination with computational target predictions, are consistent with miRNAs regulating a broad spectrum of physiological and developmental processes. HHS Public AccessMicroarray-based expression studies have indicated specific alterations in human miRNA expression profiles that correlate with particular tumour phenotypes (J.M.T. and S.M.H., unpublished data). Among those that show altered expression, the mir-17-92 cistron is located at 13q31, a genomic locus that is amplified in cases of diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, primary cutaneous B-cell lymphoma and several other tumour types 1,13 . There are only two annotated genes in the epicentre of this amplicon, c13orf25 and GPC5. Previous studies have shown that c13orf25 is the only one of the two genes for which increased expression correlates with the presence of the amplicon 1 . The...

MicroRNAs (miRNAs) are ∼22-nucleotide RNAs that can pair to sites within messenger RNAs to specify posttranscriptional repression of these messages. Aberrant miRNA expression can contribute to tumorigenesis, but which of the many miRNA-target relationships are relevant to this process has been unclear. Here, we report that chromosomal translocations previously associated with human tumors disrupt repression of High Mobility Group A2 (Hmga2) by let-7 miRNA. This disrupted repression promotes anchorage-independent growth, a characteristic of oncogenic transformation. Thus, losing miRNA-directed repression of an oncogene provides a mechanism for tumorigenesis, and disrupting a single miRNA-target interaction can produce an observable phenotype in mammalian cells.