Abstract B43: Role of activated SHP2 in high-risk neuroblastoma pathogenesis

Abstract

Abstract Neuroblastoma, an embryonic tumor of peripheral sympathetic nervous system (PSNS), accounts for 10% of all childhood cancer deaths. We recently developed a robust zebrafish model of neuroblastoma and demonstrated that activated ALK synergizes with MYCN by inhibiting a developmentally-timed apoptotic response that is otherwise induced by MYCN. Genomic studies show that PTPN11 (encoding SHP2) is the second most frequently mutated genes in high-risk neuroblastoma. We have now used our zebrafish model to ask whether mutationally activated SHP2 functions as an oncogene in neuroblastoma. We developed transgenic lines in which ptpn11E69K is overexpressed in the PSNS under control of the dopamine-beta-hydroxylase promoter. Interestingly, ptpn11E69Ksynergized with MYCN to accelerate the onset of neuroblastoma in the interrenal gland, the zebrafish analogue of the adrenal medulla. Tumors began to appear at 15 weeks in transgenic fish overexpressing MYCN alone, whereas latency was shortened to 7 weeks and the penetrance was increased more than four-fold in transgenic fish co-expressing MYCN and ptpn11E69K. Co-expression of ptpn11E69K and MYCN also induced ganglioneuroma in the sympathetic ganglia, an outcome that has not been observed in transgenic fish overexpressing MYCN and activated ALK. These results suggest that activated SHP2 can collaborate with MYCN in neuroblastoma tumorigenesis via mechanisms different from those of activated ALK. Thus, zebrafish appears to provide a robust model system for functional genomic analysis and for the investigation of the mechanisms and pathways underlying mutations identified in ongoing tumor resequencing studies. Citation Format: (Jane) shizhen Zhu, Benjamin G. Neel, A. Thomas Look. Role of activated SHP2 in high-risk neuroblastoma pathogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B43.