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Somatic cell transfer of c-Myc and Bcl-2 induces large-cell anaplastic medulloblastomas in mice

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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.

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Acknowledgments

The authors thank Kristin Kraus (University of Utah) for editorial assistance. This work was supported by Grants from the National Institutes of Health (R01CA18622 to DWF and K08NS070928 to GR) and the Huntsman Cancer Institute of the University of Utah (P30CA042014 to DF).

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Authors and Affiliations

  1. Department of Neurosurgery and Huntsman Cancer Institute, University of Utah School of Medicine, 175 North Medical Drive East, Salt Lake City, UT, 84132, USA

    Noah C. Jenkins, Carolyn A. Pedone & Daniel W. Fults

  2. Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    Ganesh Rao

  3. Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Charles G. Eberhart

  4. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA

    Adrian M. Dubuc

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  1. Noah C. Jenkins
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Correspondence to Daniel W. Fults.

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11060_2015_1985_MOESM1_ESM.tif

Supplementary Fig. 1. Comparative expression of Myc and prosurvival Bcl-2 family member genes in human Group 3 medulloblastomas. The color-coded Z-score for each tumor specimen is the number of standard deviations that the expression level of a gene is shifted above (red) or below (blue) the mean. Z-scores are shown for a discovery cohort (n = 46) and an independent validation cohort (n = 51). Purple bars below indicate tumors in which expression of both Myc and Bcl-2 was increased. Supplementary material 1(TIFF 1171 kb)

11060_2015_1985_MOESM2_ESM.tif

Supplementary Fig. 2. Kaplan–Meier survival analysis of mice after retroviral transfer of Shh and Myc + Bcl-2. The mice were injected with RCAS-SHH or RCAS-Myc and RCAS-Bcl-2 on day zero and sacrificed at the indicated time points. Supplementary material 2 (TIFF 8237 kb)

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Jenkins, N.C., Rao, G., Eberhart, C.G. et al. Somatic cell transfer of c-Myc and Bcl-2 induces large-cell anaplastic medulloblastomas in mice. J Neurooncol 126, 415–424 (2016). https://doi.org/10.1007/s11060-015-1985-9

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  • DOI: https://doi.org/10.1007/s11060-015-1985-9

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