OMIC-03. TRANSLATIONAL CONTROL IN MYC AND MYCN MEDULLOBLASTOMA

Medulloblastoma has been extensively characterized at the genomic and transcriptional levels, but little is known about how alterations in translational control underlie tumor development. Myc and Mycn are often deregulated in medulloblastoma and play important roles in tumor initiation, maintenance and progression. Although both proteins have similar structures and are functionally redundant in hindbrain development, their amplification in cerebellar granule neural precursor cells leads to different medulloblastoma subtypes. In this project we are employing ribosome profiling on mouse medulloblastoma tumors generated from granule neural precursor cells with enforced expression of Myc or Mycn. Ribosome-protected mRNA sequencing allows us to quantitatively assess the specific transcripts regulated at the level of translation, identify translation regulatory sequences within the mammalian transcriptome, and understand genotype-to-phenotype processes. We discovered that Myc- and Mycn-driven tumors exhibit many more changes at the translational rather than at the transcriptional level. In particular, we found that Mycn-driven medulloblastoma upregulates the translation of Myc target genes, while mRNA levels of those genes show no difference between Myc- and Mycn-driven tumors. Furthermore, we find that the most significant translationally upregulated Myc target genes in the Mycn tumors are transcripts that encode ribosome biogenesis factors. We will further study the role of Myc and Mycn on translational regulation of the medulloblastoma transcriptome using our xenograft model of human iPSC-derived neuroepithelial stem cells overexpressing Myc or Mycn. Our goal is to understand the regulatory function of the translational landscape in Myc- and Mycn-driven medulloblastoma and to decipher the oncogenic signaling cascades leading to different medulloblastoma subtypes.