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Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Sonic Hedgehog (SHH) signaling drives a minority of MB, correlating with desmoplastic pathology and favorable outcome. The majority, however, arises independently of SHH and displays classic or large cell anaplastic (LCA) pathology and poor prognosis. To identify common signaling abnormalities, we profiled mRNA, demonstrating misexpression of  MYCN  in the majority of human MB and negligible expression in normal cerebella. We clarified a role in pathogenesis by targeting  MYCN  (and luciferase) to cerebella of transgenic mice.  MYCN -driven MB showed either classic or LCA pathologies, with Shh signaling activated in ∼5% of tumors, demonstrating that  MYCN  can drive MB independently of Shh. MB arose at high penetrance, consistent with a role for  MYCN  in initiation. Tumor burden correlated with bioluminescence, with rare metastatic spread to the leptomeninges, suggesting roles for  MYCN  in both progression and metastasis. Transient pharmacological down-regulation of  MYCN  led to both clearance and senescence of tumor cells, and improved survival. Targeted expression of  MYCN  thus contributes to initiation, progression, and maintenance of MB, suggesting a central role for  MYCN  in pathogenesis.

Pleiotropic role forMYCNin medulloblastoma