Pleiotropic role for MYCN in medulloblastoma

Fredrik J. Swartling, Matthew R. Grimmer, Christopher S. Hackett, Paul A. Northcott, Qi Wen Fan, David D. Goldenberg, Jasmine Lau, Selma Masic, Kim Nguyen, Slava Yakovenko, Xiao Ning Zhe, Heather C. Flynn Gilmer, Rodney Collins, Mai Nagaoka, Joanna J. Phillips, Robert B. Jenkins, Tarik Tihan, Scott R. Vandenberg, C. David James, Kohichi TanakaMichael D. Taylor, William A. Weiss, Louis Chesler

Research output: Contribution to journalArticle

109 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1059-1072
Number of pages14
JournalGenes and Development
Volume24
Issue number10
DOIs
StatePublished - May 15 2010

Keywords

  • Cerebellum
  • Large cell anaplastic
  • Medulloblastoma
  • N-myc
  • Oncogene addiction
  • SHH-independent

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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  • Cite this

    Swartling, F. J., Grimmer, M. R., Hackett, C. S., Northcott, P. A., Fan, Q. W., Goldenberg, D. D., Lau, J., Masic, S., Nguyen, K., Yakovenko, S., Zhe, X. N., Flynn Gilmer, H. C., Collins, R., Nagaoka, M., Phillips, J. J., Jenkins, R. B., Tihan, T., Vandenberg, S. R., James, C. D., ... Chesler, L. (2010). Pleiotropic role for MYCN in medulloblastoma. Genes and Development, 24(10), 1059-1072. https://doi.org/10.1101/gad.1907510