title: Somatic cell transfer of c-Myc and Bcl-2 induces large-cell anaplastic medulloblastomas in mice.
abstract: A highly aggressive subgroup of the pediatric brain tumor medulloblastoma is characterized by overexpression of the proto-oncogene c-Myc, which encodes a transcription factor that normally maintains neural progenitor cells in an undifferentiated, proliferating state during embryonic development. Myc-driven medulloblastomas typically show a large-cell anaplastic (LCA) histological pattern, in which tumor cells display large, round nuclei with prominent nucleoli. This subgroup of medulloblastoma is therapeutically challenging because it is associated with a high rate of metastatic dissemination, which is a powerful predictor of short patient survival times. Genetically engineered mouse models have revealed important insights into the pathogenesis of medulloblastoma and served as preclinical testing platforms for new therapies. Here we report a new mouse model of Myc-driven medulloblastoma, in which tumors arise in situ after retroviral transfer and expression of Myc in Nestin-expressing neural progenitor cells in the cerebella of newborn mice. Tumor induction required concomitant loss of Tp53 or overexpression of the antiapoptotic protein Bcl-2. Like Myc-driven medulloblastomas in humans, the tumors induced in mice by Myc + Bcl-2 and Myc - Tp53 showed LCA cytoarchitecture and a high rate of metastatic dissemination to the spine. The fact that Myc - Tp53 tumors arose only in Tp53(-/-) mice, coupled with the inefficient germline transmission of the Tp53-null allele, made retroviral transfer of Myc + Bcl-2 a more practical method for generating LCA medulloblastomas. The high rate of spinal metastasis (87% of brain tumor-bearing mice) will be an asset for testing new therapies that target the most lethal aspect of medulloblastoma.
authors.affiliation: Department of Neurosurgery and Huntsman Cancer Institute, University of Utah School of Medicine, 175 North Medical Drive East, Salt Lake City, UT, 84132, USA.
authors.forename: Noah C
authors.initials: NC
authors.lastname: Jenkins
authors.affiliation: Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Rao
authors.affiliation: Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.affiliation: Department of Neurosurgery and Huntsman Cancer Institute, University of Utah School of Medicine, 175 North Medical Drive East, Salt Lake City, UT, 84132, USA.
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Pedone
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Dubuc
authors.affiliation: Department of Neurosurgery and Huntsman Cancer Institute, University of Utah School of Medicine, 175 North Medical Drive East, Salt Lake City, UT, 84132, USA. daniel.fults@hsc.utah.edu.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Fults
mesh_terms: D000818:Animals; D018287:Carcinoma, Large Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D008297:Male; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: C000715470:MAS1 protein, human; C489428:Myc protein, mouse; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53
keywords: Bcl-2; Medulloblastoma; Mouse model; Myc; Spinal metastasis