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The  miR-17∼92  cluster is a potent microRNA-encoding oncogene. Here, we show that  miR-17∼92  synergizes with loss of  Rb  family members to promote retinoblastoma. We observed  miR-17∼92  genomic amplifications in murine retinoblastoma and high expression of  miR-17∼92  in human retinoblastoma. While  miR-17∼92  was dispensable for mouse retinal development,  miR-17∼92  overexpression, together with deletion of  Rb  and  p107 , led to rapid emergence of retinoblastoma with frequent metastasis to the brain.  miR-17∼92  oncogenic function in retinoblastoma was not mediated by a  miR-19 /PTEN axis toward apoptosis suppression, as found in lymphoma/leukemia models. Instead,  miR-17∼92  increased the proliferative capacity of  Rb / p107 -deficient retinal cells. We found that deletion of  Rb  family members led to compensatory up-regulation of the cyclin-dependent kinase inhibitor p21Cip1.  miR-17∼92  overexpression counteracted p21Cip1 up-regulation, promoted proliferation, and drove retinoblastoma formation. These results demonstrate that the oncogenic determinants of  miR-17∼92  are context-specific and provide new insights into  miR-17∼92  function as an  RB -collaborating gene in cancer.

miR-17∼92 cooperates with RB pathway mutations to promote retinoblastoma