Overexpression of MYCN overcomes a proliferative block to drive RB-deficient retinoblastoma.

  • Major finding: Overexpression of MYCN overcomes a proliferative block to drive RB-deficient retinoblastoma.

  • Clinical relevance: Conditional expression of Mycn was induced in retinal progenitor cells in Rb-null mice.

  • Impact: A mouse model recapitulates human retinoblastoma and provides insight into the role of MYCN.

Most retinoblastomas (RB) that exhibit MYCN amplification also harbor RB mutations, whereas a small subset of MYCN-amplified RBs harbors wild-type RB. Although it is known that MYCN regulates cellular processes such as proliferation and global chromatin organization, the role of MYCN in RB has not been fully elucidated, nor has it been ascertained whether therapeutic targeting of MYCN would give rise to MYCN-independent tumors. To determine how MYCN cooperates with RB loss to drive RB and whether MYCN is required for RB maintenance, Wu and colleagues inducibly overexpressed Mycn in mouse models of Rb-deficient RB. Inducible overexpression of MYCN during retinal development reduced the latency of retinoblastomas in mice harboring the co-deletion of Rb and an RB family member, which is required for murine Rb−/− RB formation, and promoted RB in Rb−/− mice. Further, Mycn+;Rb−/− retinae exhibited increased expression of MYC- and E2F-associated genes, suggesting that MYCN activates proliferation transcriptional programs in Rb−/− cells to drive RB formation in lieu of the deletion of another RB family member. Loss of induced Mycn expression in Rb-null retinoblastoma cells resulted in reduced proliferation, senescent features, and increased repressive chromatin marks in vitro. In vivo, however, while the short-term loss of induced Mycn expression resulted in cell-cycle arrest and tumor regression, prolonged suppression of Mycn resulted in increased retinal proliferation, and long-term suppression of Mycn resulted in the emergence of Mycn-independent tumors. Copy-number variation analyses revealed that a subset of Mycn-independent tumors harbored focal amplification of miR-17-92, a key MYCN target gene involved in cell growth–related processes; however, miR-17-92 overexpression could not rescue proliferation in Mycn-suppressed RB cells in vitro. Together, these results describe a mouse model of RB driven by concomitant Mycn overexpression and Rb loss that recapitulates the human disease, provide insight into the role of MYCN in RB tumorigenesis, and identify a potential mechanism underlying resistance to MYCN-targeted therapies.

Wu N, Jia D, Bates B, Basom R, Eberhart CG, MacPherson D. A mouse model of MYCN-driven retinoblastoma reveals MYCN-independent tumor reemergence. J Clin Invest; 2017 Feb 6 [Epub ahead of print].