Abstract 357: A glial origin for medulloblastoma and inhibition of MYCN stabilization

The origin of MYCN-driven medulloblastoma, a poor-prognosis childhood brain tumor is not known. We recently showed that MYCN could generate tumors with high penetrance from a glutamate transporter (GLT1) promoter in a transgenic model (GTML) of medulloblastoma. By using Rosa26-lsl-LacZ reporters we also showed that GLT1-positive neural stem cells (NSCs) from normal brain represent putative cells of tumor origin. GTML mice generate aggressive MYCN-driven medulloblastoma 2-3 months after birth. BrdU-labeling of 3-week-old GTML mice detected significantly more proliferation in thalamic forebrain cells and of BrdU/BLBP-double positive Bergmann glia in the cerebellum as compared to corresponding normal brain. Retroviral tagging with the RCAS/tv-a system marked BLBP- or GFAP-positive tumor initiating cells and expression analysis could further determine genetic profiles of tumor origin. Interestingly, MYCN levels and early proliferation of brain tumors could be reduced by specific inhibition of CDK2 or by using the bromodomain inhibitor JQ1. Both treatment strategies induced tumor cell senescence as seen by SA-beta-gal activity and by downregulated Lamin B1. Our results propose a radial glial or a Bergmann glial origin for MYCN-driven medulloblastoma and further suggest ways to inhibit tumor growth by repressing MYCN stabilization. Citation Format: Sara Bolin, Jasmine Lau, Vasil Savov, Justin Chen, Anders I. Persson, Sanna-Maria Hede, William A. Weiss, Fredrik J. Swartling. A glial origin for medulloblastoma and inhibition of MYCN stabilization. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 357. doi:10.1158/1538-7445.AM2013-357