MicroRNA-17∼92 plays a causative role in lymphomagenesis by coordinating multiple oncogenic pathways

MicroRNAs (miRNAs) have been broadly implicated in cancer, but their exact function and mechanism in carcinogenesis remain poorly understood. Elevated miR-17 similar to 92 expression is frequently found in human cancers, mainly due to gene amplification and Myc-mediated transcriptional upregulation. Here we show that B cell-specific miR-17 similar to 92 transgenic mice developed lymphomas with high penetrance and that, conversely, Myc-driven lymphomagenesis stringently requires two intact alleles of miR-17 similar to 92. We experimentally identified miR-17 similar to 92 target genes by PAR-CLIP and validated select target genes in miR-17 similar to 92 transgenic mice. These analyses demonstrate that miR17 similar to 92 drives lymphomagenesis by suppressing the expression of multiple negative regulators of the PI3K and NF kappa B pathways and by inhibiting the mitochondrial apoptosis pathway. Accordingly, miR-17 similar to 92-driven lymphoma cells exhibited constitutive activation of the PI3K and NF kappa B pathways and chemical inhibition of either pathway reduced tumour size and prolonged the survival of lymphoma-bearing mice. These findings establish miR-17 similar to 92 as a powerful cancer driver that coordinates the activation of multiple oncogenic pathways, and demonstrate for the first time that chemical inhibition of miRNA downstream pathways has therapeutic value in treating cancers caused by miRNA dysregulation.