OVEREXPRESSION OF MYC ALONE IS SUFFICIENT TO INITIATE GROUP 3 MEDULLOBLASTOMA

Medulloblastoma (MB) is the most common malignant brain tumor in children. Among the four molecular subgroups of MB (WNT, SHH, Group 3 and Group 4), patients with Group 3 MB exhibit the worst prognosis. Group 3 MB is associated with amplification and overexpression of the MYC oncogene. However, whether MYC overexpression alone is sufficient to induce Group 3 MB tumorigenesis in specific cell type(s) in the cerebellum remains unclear. The study of the etiology of Group 3 MB and the development of effective, targeted therapies for this disease has also been impeded by lack of appropriate disease models that faithfully recapitulate Group 3 MB. Here, we generated a novel mouse model for Group 3 MB and demonstrated that overexpression of MYC alone is sufficient to transform astrocyte progenitors and granule neuron progenitors in the early postnatal cerebellum. The resulting tumors resemble human Group 3 MB in terms of histology and gene expression profiles, making this animal model a valuable tool for the development and testing of new therapies. To identify potential therapeutic targets, we analyzed dysregulated gene expression and revealed that the genes involved in the glucose metabolism pathways were significantly upregulated in murine and human Group 3 MB compared to normal cerebellar cells or SHH Group MB. Among these genes, expression of lactate dehydrogenase A (LDHA), which catalyzes the conversion of pyruvate to lactate during energy metabolism, is associated with poor prognosis in Group 3 MB. Inhibition of LDHA by either RNA interference or pharmacological agents significantly reduced growth of both mouse and human Group 3 tumor cells, without affecting SHH Group MB, suggesting that LDHA is a potential specific target for treating Group 3 MB.