Abstract
Abstract Ewing's sarcoma family of tumors (ESFT) regroups mesenchymal tumors of bone and soft tissues that affect mostly children and young adults. ESFT is characterized by genetic lesions that include chromosomal translocations that generate de novo chimeric fusion oncoproteins between the TLS/EWS/TAF15 family of RNA-binding proteins and members of the ETS family of transcription factors. Contrary to the progress made in uncovering the genetic bases of Ewing's sarcoma, much remains to be discovered in the epigenetic mechanisms underlying ESFT pathogenesis. We have recently shown that alterations in the expression of EZH2 (a.k.a. KMT6), a methyltransferase that catalyzes the H3K27me3 mark, and of LSD1 (a.k.a. KDM1A), an H3K4me3 demethylase, contribute to ESFT pathology and can be targeted with drugs to curtail Ewing's sarcoma cell growth in vitro (EZH2 and LSD1) and in vivo (EZH2). To start deciphering the contribution of epigenetic modifiers to ESFT pathology, we surveyed the expression of all known histone modifying enzymes (HMEs) in four ESFT patient cohorts, totaling 96 tumors. We used the Ican analytical method to infer gene expression significance compared to a mesenchymal stem cell benchmark, as previously reported (Clin. Cancer Res 16: 3769-78, 2010). We show that, in addition to EZH2 and LSD1, several HMEs are up-regulated in ESFT compared to mesenchymal stem cell progenitors, indicating that the combinatorial activities of several HMEs are likely to promote an ESFT-specific epigenomic landscape. These findings represent the first extensive analysis of HMEs in ESFT, suggest a role of HMEs in ESFT pathogenesis and/or maintenance, and offer putative drug targets that may provide much needed novel ESFT epigenetic therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1062. doi:1538-7445.AM2012-1062
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