CBMT-34. TARGETING THE RNA-PROCESSING GENE MAGOH AS A NOVEL THERAPY FOR MEDULLOBLASTOMA

Abstract

We have proposed that microcephaly-producing mutations identify genes required for growth in the nervous system that may be new targets for brain tumor treatment. We tested this hypothesis by deleting the RNA-processing gene Magoh during cerebellar development and medulloblastoma pathogenesis. Magoh mutation has been shown to induce DNA damage and apoptosis in forebrain progenitors, resulting in microcephaly. We conditionally deleted Magoh during postnatal cerebellar neurogenesis by crossing Magoh^loxP/loxP mice with CAG-CreER transgenic mice (Magoh^Cre-ER). Magoh-deleted cerebellar granule neuron progenitors (CGNPs) of the cerebellum of Magoh^Cre-ER mice showed DNA damage, cell cycle arrest and apoptosis, which depleted the progenitor-rich external granule layer within 72 hrs. Moreover, deleting Magoh in SHH-driven medulloblastomas in SmoA1 mice similarly induced DNA damage, apoptosis and tumor shrinkage. These data show that MAGOH is required for SHH-driven proliferation in both normal cerebellar progenitors and in SHH-driven medulloblastoma. These findings are the first to show that medulloblastoma growth can be disrupted by targeting the RNA processing machinery.