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Katherine Veleta, Andrew Crowther, Timothy Gershon, PM-07
Bcl-xL DEPENDENCE OF NEURAL PROGENITORS MAY BE EXPLOITED TO IMPROVE MEDULLOBLASTOMA THERAPY, Neuro-Oncology, Volume 17, Issue suppl_3, June 2015, Page iii32, https://doi.org/10.1093/neuonc/nov061.129Close - Share Icon Share
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Medulloblastoma is markedly more sensitive to radiation and chemotherapy than glioblastoma or PNET, but the underlying mechanisms contributing to this sensitivity remain unknown. Identifying the molecular mechanisms that mediate sensitivity of medulloblastoma to radiation and chemotherapy may lead to more targeted, less toxic approaches to therapy. We have previously shown that cerebellar neuronal progenitors (CGNPs), the cells of origin for Shh-driven medulloblastoma, are primed for rapid apoptosis in response to DNA damage, and that this apoptotic mechanism is conserved in medulloblastoma. In CGNPs and medulloblastoma cells, the pro-apoptotic protein Bax is maintained in an active conformation at mitochondria, complexed with its anti-apoptotic homolog, Bcl-xL. In this study we have examined the consequences of disrupting Bcl-xL in CGNPs and medulloblastoma cells in vivo, using conditional genetic deletion. We found that deleting Bcl-xL from CGNPs during development caused cerebellar hypoplasia by dramatically increasing CGNP apoptosis. In medulloblastoma-prone SmoM2 mice, deletion of Bcl-xL markedly decreased tumor growth, leaving large acellular spaces indicative that regions of the tumor had undergone apoptosis. Our findings suggest that therapeutic agents specifically targeting Bcl-xL may directly activate apoptotic pathways in medulloblastoma in the absence of DNA damage, potentially decreasing the toxicity associated with conventional treatments such as radiation therapy.
