Abstract LB-149: Identification of novel genes that cooperate with increased eIF4E expression to generate medulloblastoma using the Sleeping Beauty transposon system

Abstract

Abstract Medulloblastoma is a malignant brain tumor that arises in the cerebellum of young children and occasionally is observed in adults. Increasing evidence suggests that different cell populations represent distinct cells of origin for the various medulloblastoma subtypes, and that these subtypes can be associated with aberrant activation of specific signaling pathways. Current mouse models recapitulate the Shh pathway driven tumors however few models are available to study other medulloblastoma subtypes as genetic events that drive tumorigenesis remain unknown. To address this problem we used the Sleeping Beauty transposon system to uncover novel mutations that contribute to medulloblastoma. Based on earlier work in normal CGNPs, we found that the translation initiation factor eIF4E is critical for regulating CGNP proliferation and the mRNA translation machinery is uniformly upregulated across medulloblastoma subtypes. Using a mouse model wherein eIF4E is ubiquitously over-expressed under control of the -actin promoter (T-Eif4e) we investigated cerebellum development and found that the CGNPs have increased proliferation in vitro in the absence of Shh as well as an expanded proliferative zone in vivo; however these mice do not develop medulloblastoma. Because eIF4E is an oncogene and been shown to cooperate with other known oncogenes in different cell types to accelerate tumorigenesis, we investigated whether eIF4E can cooperate with other mutated genes to generate medulloblastoma. Using a CGNP-specific promoter to drive transposase expression (“Math1-SB”), we crossed these mice with two different lines that carry the Sleeping Beauty transposon (T2/Onc 68 or T2/Onc 76) on different chromosomes. The progeny were then crossed with the T-Eif4e mice and observed for medulloblastoma occurrence; no tumors arise as a result of Math1-SB-mediated transposase activity alone. However, compared to the latency of tumors generated in SmoA1 mice, which have constitutive activation of the Shh pathway, tumors in T-eIF4E/Math1-SB/T2Onc animals arose earlier and were highly proliferative based on Ki-67 staining. They also expressed Otx2, which is associated with a medulloblastoma subtype that does not contain Shh or Wnt pathway mutations. Sequencing of the tumors to identify the genes whose activity is induced (novel oncogenes) or repressed (novel tumor suppressors) by transposon insertion will reveal genes that cooperate with eIF4E to induce medulloblastoma, and may lead to development of new mouse models for medulloblastoma as well as increased insight into genetic events contributing to these tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-149.