Here we report that high-level MDM2 but not MDM4 has a consistent critical role in retinoblastoma cell proliferation in vitro, as well as in orthotopic xenografts.
MDM2 or MDM4 gene amplification is only associated with the wild-type TP53 gene in retinoblastomas, thus the amplification of the two genes is mutually exclusive.
Our results demonstrated that some copy number changes thought to belong to early (MDM4 gain) or late stage (MYCN and E2F3 gain) of retinoblastoma are already present in retinoma at the same (for MDM4) or at lower (for MYCN and E2F3) copy number variation respect to retinoblastoma.
In both genetic contexts, the TP53 pathway was inactivated by genetic lesions and not by the activation of the ARF/MDM2/MDMX pathway, as recently shown in retinoblastomas.