Abstract 3413: Tumor-specific transcriptional control networks regulating DNA replication genes in Ewing's sarcoma

Surveillance of DNA replication licensing is often perturbed in cancer cells allowing for genomic aberrations. Although this process contributes to cellular transformation, it is not well understood to what extent and how oncogenes might deregulate genes involved in DNA replication and in the control of replication licensing. Previous findings on the EWS-FLI1 fusion oncogene (which is the genetic hallmark Ewing's sarcoma), and our recent findings on MYC targets in this aggressive childhood tumor suggested that both these oncogenes constitute a regulatory feed-back loop. Our gene expression data from Ewing's cells in which MYC had been knocked down, we propose that MYC mediates at least part of the oncogenic EWS-FLI1 functions since it controls most essential biological functions required for cell proliferation. Gene expression correlation and gene set enrichment analysis in tumors and cell lines suggests the MYC/EWS-FLI1 loop as a central regulator in a regulatory network that controls DNA replication. To further narrow down the target gene repertoire and to identify direct transcriptional targets, we performed a genome wide chromatin-immunoprecipitation study using an anti MYC antibody in combindation with ChIP/CHIP analysis. We further extended our model whereby the core EWS-FLI1/MYC feedback loop could be linked to other candidate transcriptional regulators of DNA replication. Several replication licensing genes including MCM, ORC or licensing control genes such as CDT1 and CDC6 were found to be under direct and/or indirect control of the MYC/EWS-FLI1 loop and their associated transcription factor network. A subset of DNA replication genes is particularly deregulated in Ewing's cells when compared to mesenchymal progenitor cells that are considered the tissue of origin of Ewing's sarcoma. When comparing Ewing's sarcoma with other childhood tumors such as e.g. neuroblastoma, we found Ewing's-specific versus more general regulatory connections between the MYC/EWS-FLI1 loop and DNA replication genes. Together, our data provide first insight into a newly defined MYC/EWS-FLI1-driven regulatory network underlying transcriptional DNA replication control. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 3413.