MDM2 as MYCN transcriptional target: implications for neuroblastoma pathogenesis.

MYCN amplification is associated with an exceptionally poor prognosis in neuroblastoma. Furthermore, the crucial effectors of MYCN responsible for this aggressive subset of neuroblastoma await characterization. A critical negative regulator of the p53 tumor suppressor, MDM2, has been recently characterized in neuroblastoma cell lines as a transcriptional target of MYCN. Targeted inhibition of MYCN results in reduced MDM2 expression levels, with concomitant stabilization of p53 and stimulation of apoptosis in MYCN amplified neuroblastoma cell lines. These data suggest the possibility that MYCN-driven expression of MDM2 might play a role in counterbalancing the p53-dependent apoptotic pathways concurrently stimulated by over expression of MYC proteins. Mouse models of lymphoma have demonstrated that MDM2 expression, with decreased p53 activity, is critical for complete MYCC driven tumorigenesis. Our data suggest that a similar situation may apply for MYCN in neuroblastoma. Strategies for pharmacologic and genetic inhibition of MDM2 may prove to be an important new therapeutic approach in neuroblastoma.