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Pleiotropic role for MYCN in medulloblastoma
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. (Swartling)
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2010 (English)In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 24, no 10, 1059-1072 p.Article in journal (Refereed) Published
Abstract [en]

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 approximately 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.

Place, publisher, year, edition, pages
2010. Vol. 24, no 10, 1059-1072 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-152185DOI: 10.1101/gad.1907510PubMedID: 20478998OAI: oai:DiVA.org:uu-152185DiVA: diva2:412849
Funder
Swedish Research Council, 2007-7983
Available from: 2011-04-26 Created: 2011-04-26 Last updated: 2017-12-11Bibliographically approved

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Swartling, Fredrik Johansson

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