NEOPLASIA

mutated/amplified in tumors, represents an important regulator of cell growth be-cause of its ability to induce both prolifera-tion and apoptosis. Recent evidence links MYC to altered miRNA expression, thereby suggesting that MYC-regulated miRNAs might contribute to tumorigen-esis. To further analyze the impact of MYC-regulated miRNAs, we investigated a murine lymphoma model harboring the MYC transgene in a Tet-off system to control its expression. Microarray-based miRNA expression profiling revealed both known and novel MYC targets. Among the miRNAs repressed by MYC, we identified the potential tumor suppressor miR-26a, which possessed the ability to attenuate proliferation in MYC-dependent cells. In-terestingly, miR-26a was also found to be deregulated in primary human Burkitt lym-phoma samples, thereby probably being of clinical relevance. Although today only few miRNA targets have been identified in human disease, we could show that ec-topic expression of miR-26a influenced cell cycle progression by targeting the bona fide oncogene EZH2, a Polycomb protein and global regulator of gene ex-pression yet unknown to be regulated by miRNAs. Thus, in addition to directly tar-geting protein-coding genes, MYC modu-lates genes important to oncogenesis via deregulation of miRNAs, thereby vitally contributing to MYC-induced lym-phomagenesis. (Blood. 2008;112: 4202-4212