Abstract 356: Role of the LMO1 oncogene in neuroblastoma pathogenesis.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Neuroblastoma, an embryonic tumor of the 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 (Zhu et.al. Cancer Cell, 2012). We have now used this model to provide evidence in support of the results of a neuroblastoma genome-wide association study (GWAS) showing that common variation within the LIM domain-only 1 (LMO1) gene locus is highly associated with the development of advanced neuroblastoma and may function as an oncogene in established disease (Wang K et.al. Nature, 2011). We are collaborating because our zebrafish system provides a robust in vivo tumor model to investigate the underlying mechanisms through which LMO1 overexpression contributes to malignant transformation. Here we developed transgenic lines in which LMO1 is overexpressed in the PSNS under control of the dopamine-beta-hydroxylase (dβh) promoter. We observed that overexpression of LMO1 in three individual transgenic lines synergized with MYCN to accelerate the onset of neuroblastoma in the interrenal gland (IRG), the zebrafish analogue of the adrenal medulla. Tumors began to appear at 13 weeks in transgenic fish overexpressing MYCN alone and this latency was shortened dramatically to 5 weeks (p=0.02) and the penetrance was increased more than three-fold in the transgenic fish coexpressing both MYCN and LMO1. In addition, we found that coexpression of LMO1 with activated ALK induced neuroblastoma, which is the first time in our model system that neuroblastoma has been induced without MYCN overexpression. Thus, the zebrafish model system appears to be robust for “functional genomics analysis” to provide in vivo evidence and investigate mechanisms and pathways underlying new associations emerging from GWAS, tumor genome resequencing and other genome-wide technologies that are currently under intense investigation in human cancers. Citation Format: Shizhen Zhu, Andrew Wood, Shuning He, Rebecca Stanton, Feng Guo, John Maris, A. Thomas Look. Role of the LMO1 oncogene in neuroblastoma pathogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 356. doi:10.1158/1538-7445.AM2013-356