The c-Myc oncogenic transcription factor is pathologically activated in many human malignancies. Myc is known to directly upregulate a pro-tumorigenic group of microRNAs (miRNAs) known as the miR-17-92 cluster. However, through analysis of human and mouse models of B cell lymphoma, the study reveals that Myc regulates a much broader set of miRNAs than previously anticipated. Unexpectedly, the predominant consequence of Myc activation is widespread repression of miRNA expression. Chromatin immunoprecipitation (ChIP) studies indicate that much of this repression is likely due to Myc binding to miRNA promoters. The study further shows that enforced expression of repressed miRNAs diminishes the tumorigenic potential of lymphoma cells. These results demonstrate that extensive reprogramming of the miRNA transcriptome by Myc contributes to tumorigenesis. Myc dysregulated expression or function occurs frequently in human malignancies. Through positive and negative regulation of an extensive network of target genes, Myc globally reprograms cells to drive proliferation and, in some settings, induce cell death. Myc uses distinct mechanisms for activating and repressing gene expression. When inducing transcription, Myc dimerizes with its binding partner Max and binds to genomic DNA directly upstream or within the first introns of target genes. When repressing transcription, Myc does not seem to contact DNA directly. Rather, Myc is recruited through protein-protein interactions to core promoters, where it antagonizes the activity of positive regulators of transcription. For example, Myc can bind to and inhibit the activity of the transcription factor Myc-interacting zinc finger protein 1 (Miz1), thereby preventing Miz1 from activating transcription of the CDKN1A (also known as p21) and CDKN2B (p15) cell cycle-inhibitory genes. Repression of other Myc targets is probably mediated through the ability of Myc to interact with and antagonize the activity of additional transcriptional regulators, including Sp1, Smad2 and NF-Y. miRNAs are a diverse family of RNA molecules, typically 18-24 nucleotides in length, that have emerged as a class of Myc-regulated transcripts. miRNAs regulate the stability and translational efficiency of partially complementary target mRNAs. miRNAs are initially transcribed by RNA polymerase II as long primary transcripts (pri-miRNAs) that are capped, polyadenylated and frequently spliced. The mature miRNA sequences are located in introns or exons of pri-miRNAs, within regions that fold into hairpin structures of approximately 60-80 nucleotides. Although most pri-miRNAs are noncoding transcripts, some miRNAs are located within introns of protein-coding genes. miRNA maturation requires a series of endThe c-Myc oncogenic transcription factor is pathologically activated in many human malignancies. Myc is known to directly upregulate a pro-tumorigenic group of microRNAs (miRNAs) known as the miR-17-92 cluster. However, through analysis of human and mouse models of B cell lymphoma, the study reveals that Myc regulates a much broader set of miRNAs than previously anticipated. Unexpectedly, the predominant consequence of Myc activation is widespread repression of miRNA expression. Chromatin immunoprecipitation (ChIP) studies indicate that much of this repression is likely due to Myc binding to miRNA promoters. The study further shows that enforced expression of repressed miRNAs diminishes the tumorigenic potential of lymphoma cells. These results demonstrate that extensive reprogramming of the miRNA transcriptome by Myc contributes to tumorigenesis. Myc dysregulated expression or function occurs frequently in human malignancies. Through positive and negative regulation of an extensive network of target genes, Myc globally reprograms cells to drive proliferation and, in some settings, induce cell death. Myc uses distinct mechanisms for activating and repressing gene expression. When inducing transcription, Myc dimerizes with its binding partner Max and binds to genomic DNA directly upstream or within the first introns of target genes. When repressing transcription, Myc does not seem to contact DNA directly. Rather, Myc is recruited through protein-protein interactions to core promoters, where it antagonizes the activity of positive regulators of transcription. For example, Myc can bind to and inhibit the activity of the transcription factor Myc-interacting zinc finger protein 1 (Miz1), thereby preventing Miz1 from activating transcription of the CDKN1A (also known as p21) and CDKN2B (p15) cell cycle-inhibitory genes. Repression of other Myc targets is probably mediated through the ability of Myc to interact with and antagonize the activity of additional transcriptional regulators, including Sp1, Smad2 and NF-Y. miRNAs are a diverse family of RNA molecules, typically 18-24 nucleotides in length, that have emerged as a class of Myc-regulated transcripts. miRNAs regulate the stability and translational efficiency of partially complementary target mRNAs. miRNAs are initially transcribed by RNA polymerase II as long primary transcripts (pri-miRNAs) that are capped, polyadenylated and frequently spliced. The mature miRNA sequences are located in introns or exons of pri-miRNAs, within regions that fold into hairpin structures of approximately 60-80 nucleotides. Although most pri-miRNAs are noncoding transcripts, some miRNAs are located within introns of protein-coding genes. miRNA maturation requires a series of end