Abstract IA06: Disregulation of lncRNAs helps drive Ewing sarcoma pathogenesis

Abstract

Abstract Pediatric sarcomas are orphan diseases that cause significant morbidity and mortality in children, adolescents and young adults. Among the most intriguing pediatric sarcomas is Ewing sarcoma. The (11;22)(q24;q12) translocation, which leads to expression of EWS/FLI, is identified in 85% of Ewing sarcoma cases. Ewing sarcoma cells carrying this translocation have a strict dependency on its expression, suggesting that the translocation is a critical oncogenic event in this disease. Despite intensive investigation, the mechanisms through which EWS/FLI leads to oncogenesis are incompletely understood. Recent data indicates that two distinct mechanisms are involved. In one, EWS/FLI leads to gene activation by acting as a pioneer transcription factor at novel enhancers. In another, EWS/FLI forces the removal of ets binding factors from their established binding sites and acts as a transcriptional repressor. How these two diverse functions are orchestrated at a molecular level remains unclear. Given the widespread transcription of long non-coding RNAs and their emerging role in gene regulation, they are strong candidates for participation in the complex genetic rewiring program induced by EWS/FLI. We recently described the first lncRNA clearly regulated by EWS/FLI, (EWS-associated transcript 1, EWSAT1). Expression of EWS/FLI drives upregulation of EWSAT1 most likely by direct transcriptional regulation. EWSAT1 in turn plays a critical role in EWS/FLI-mediated gene repression, at least in part by interacting with the RNA binding protein hnRNPK. RNAseq analysis indicates that EWS/FLI regulates the expression of a large number of other lncRNAs in addition to EWSAT1. We have identified lnc659 (EWSAT2) as a second Ewing sarcoma-related transcript with functional relevance to Ewing pathogenesis. EWSAT2 is upregulated by expression of EWS/FLI and knock-down of EWSAT2 strongly decreases the proliferation of Ewing sarcoma cell lines in vitro and the oncogenicity of cell lines and patient-derived xenografts in vivo. Ongoing studies are directed at identifying the molecular mechanism of action of EWSAT1 and EWSAT2 as well as other lncRNAs in the pathogenesis of Ewing sarcoma. Citation Format: Alejandro Sweet-Cordero. Disregulation of lncRNAs helps drive Ewing sarcoma pathogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr IA06.