Medulloblastomas comprise 25% of all childhood brain tumors and have a mortality of approximately 50% with a high degree of neurologic sequelae in the survivors. Little is known regarding its pathogenesis. We will study the relationship between oncogenic transformation and the block to terminal differentiation of medulloblastoma tumor cells. In Phase I, specifically: 1. We will determine the extent of differentiation of medulloblastoma tumor cells by ?robing tumor RNA for expression of a panel of nervous-system-specific, stage specific genes. 2. We will screen medulloblastoma tumor tissue for activation of known oncogenes. PreLiminary studies indicate medulloblastoma tumors express high levels of c-myc mRNA. The mechanism of activation of c-myc or other oncogenes will be determined. 3. We will use murine retrovirus vectors designed to introduce the myc (or other) oncogene into neuronal precursor cells in rodents in order to attempt to induce medulloblastoma tumors experimentally in vivo. These tumors will be employed to study further the relationship of unregulated myc (or other oncogene) expression and blocks to neuronal saturation. Next we will study the mechanistic relationship between elevated oncogene expression and the block to expression of genes activated during neuronal differentiation. In ?base II, specifically: 1. We will attempt to identify regulatory DNA sequences which function in transcription of neural specific genes. We shall focus on genes identified in Phase I whose expression is blocked as a result of transformation events in medulloblastoma cells. 2. We will identify transcription factors present in mature, differentiated neuronal ells which bind to these sequences and activate neuronal gene transcription. 3. We will characterize the levels of these same transcription factors in medulloblastoma tumor tissue, in neuronal tumors induced in Phase I in rodents by retroviral vectors', and in cell lines derived from these tumors. We will attempt to determine whether failure to activate differentiation-specific genes in these cells is a consequence of failure to express necessary transcription factors. Together these studies will define the relationship between neuronal cell transformation and blocks to cell differentiation.
| MacGregor, D N; Ziff, E B (1990) Elevated c-myc expression in childhood medulloblastomas. Pediatr Res 28:63-8 |
