Abstract 2596: SOX11 is a key epigenetic regulatorin the adrenergic MYCN amplified neuroblastomas
Authors: Amber Louwagie
Journal: Cancer Research (2019)

Abstract Neuroblastoma (NB) is a pediatric cancer of the developing sympatho-adrenergic nervous system, responsible for 15% of childhood cancer deaths. Understanding the fundamental underlying mechanisms of NB is key to early detection and appropriate treatment. High risk NBs are predominantly driven by DNA copy number alterations, including MYCN amplification, rare recurrent amplifications (affecting critical oncogenes including LIN28B, ALK and MDM2) and large 2p and 17q gains. Here we report on the role of rare recurrent focal gains and amplifications of the SRY-related HMG-box transcription factor SOX11. In a series of 842 NB samples, we observed five tumors with high-level gain or amplification of SOX11. Copy number versus mRNA expression analysis for SOX11 suggests dosage sensitivity (p=1.82e-09). Kaplan-Meier analysis in two large independent cohorts of NB primary tumors showed decreased overall survival for patients with higher SOX11 levels (p=4.19e-07) suggesting SOX11 contribution to tumor aggressiveness. SOX11 is upregulated by a super-enhancer in adrenergic neuroblastoma cells while absent in mesenchymal cells, indicating a putative role in cell identity. SOX11 knockdown in NB cell lines showed reduced colony formation capacity and G1-S cell cycle arrest indicating cellular dependency on high SOX11 levels. Integrated ChIP-, ATAC- and RNA-seq analysis revealed binding of SOX11 to promotors and enhancers and regulation of genes involved in cell cycle, DNA replication, DNA repair as well as chromatin remodeling. IP-MS analysis identified MYCN as interacting protein and SOX11 and MYCN expression levels show a positive correlation (R= 0.576, p=1.9e-26). A putative cooperativity is further suggested by a significant number (in average 26%) of common DNA binding regions including PRC2 components and accessory proteins and specific components of the SWI/SNF complex. Moreover, one of the most robustly regulated SOX11 targets is MYB, a known oncogene, presumed pioneer factor and master regulator. SOX11 was previously shown to preferentially bind to enhancer regions. In view of recent data that show that highly increased MYCN levels cause the protein to invade enhancers, we propose that SOX11 plays a well-defined developmental role in controlling the epigenetic enhancer landscape which is subsequently high-jacked through the MYCN enhancers invasion process. We will present enhancer landscaping on NB cells upon MYCN only versus MYCN/SOX11 combined knockdown as recently reported for MYCN/TBX2 (Decaesteker et al, Nat Commun, 2018). Initial tests on a panel of NB cell lines of compounds known to block MYB functionality showed effects on viability and proliferation and will be further tested in organoids and in vivo for patient-derived xenografts. In conclusion, we suggest an important role for SOX11 in cooperation with MYCN in NB development and propose the SOX11 regulated gene MYB as a novel therapeutic target in NB. Citation Format: Amber Louwagie. SOX11 is a key epigenetic regulatorin the adrenergic MYCN amplified neuroblastomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2596.