Abstract
Abstract Neuroblastoma (NB), a neural crest-derived embryonal tumor, is a heterogeneous childhood malignancy that often presents as an incurable disease. The anaplastic lymphoma receptor tyrosine kinase gene (ALK) was shown to be overexpressed, mutated or amplified in the majority of NB. The most common mutation, ALK-F1174L displayed an efficient transforming activity in vivo, and was shown in transgenic mouse models to drive NB formation and to cooperate with MYCN in the oncogenic process. In this project, we aimed at comparing the in vivo oncogenic potential of ALK-wt, with the two most frequent activating mutations ALK-F1174L (only present in sporadic NB), and ALK-R1275Q (present in familial and sporadic NB). Our strategy included the stable expression of ALK-wt and mutated variants into murine neural crest progenitor cells (JoMa1), which are the well-recognized NB progenitors. In vitro, only ALK-F1174L and ALK-R1275Q conferred an oncogenic potential to JoMa1 cells as measured by clonogenic assays. In contrast, in vivo experiments showed that JoMa1 cells expressing ALK-wt, as well as activating mutations ALK-R1275Q and ALK-F1174L rapidly produced highly aggressive tumors after subcutaneous or orthotopic (adrenal gland) implantations in nude mice. JoMa1-ALK-F1174L cells induced the fastest tumor growth as compared to JoMa1-ALK-R1275Q and JoMa1-ALK-wt cells, revealing the tremendous tumorigenic potential of ALK-F1174L cells. Interestingly, as a result from ALK activation, orthotopic tumors or their derived cell lines strongly upregulated c-myc expression. Moreover, specific ALK inhibition using TAE684, or c-myc inhibition with 10058-F4, completely abrogated the in vitro clonogenic capacity of tumor-derived cell lines. Such observations suggest that the tumorigenic potential of neural crest progenitor cells is strongly dependent on both ALK and c-myc activity. Our study demonstrates for the first time an oncogenic activity of ALK-R1275Q and ALK-wt when overexpressed in neural crest cells, and reveals the complex interactions between ALK and the myc oncogene family in neural crest cell-derived tumor formation. Citation Format: Annick Mühlethaler-Mottet, Gisèle Montavon, Marjorie Flahaut, Nicolas Jauquier, Jean-Marc Joseph, Olivier Delattre, Lukas Sommer, Isabelle Janoueix-Lerosey, Nicole Gross. Wild-type ALK and both ALK-R1275Q and ALK-F1174L activating mutations display a strong oncogenic activity in vivo in murine neural crest progenitor cells via cooperation with c-myc. [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 B59.
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