Abstract PR09: Cancer-specific retargeting of BAF complexes by a prion-like domain

• DOI: 10.1158/1538-7445.pedca17-pr09
• Publication Date: 2019-02-04T20:22:52Z
• Authors: Gaylor Boulay; Gabriel J. Sandoval; Nicolo Riggi; Sowmya Iyer; Rémi Buisson; Beverly Naigles; Mary E. Awad; Shruthi Rengarajan; Angela Volorio; Matthew J. McBride; Liliane C. Broye; Lee Zou; Ivan Stamenkovic; Cigall Kadoch; Miguel N. Rivera
• Keywords: 03 medical and health sciences; 0302 clinical medicine; 3. Good health

Abstract Alterations in transcriptional regulators can orchestrate oncogenic gene expression programs in cancer. Here we show that the BAF chromatin-remodeling complex, which is mutated in over 20% of human tumors, interacts with EWSR1, a member of a family of proteins with prion-like domains (PrLD) that are frequent partners in oncogenic fusions with transcription factors. In Ewing sarcoma, we find that the BAF complex is recruited by the EWS-FLI1 fusion protein to tumor-specific enhancers and contributes to target gene activation. This process is a neomorphic property of EWS-FLI1 compared to wild-type FLI1 and depends on tyrosine residues that are necessary for phase transitions of the EWSR1 prion-like domain. Furthermore, fusion of short fragments of EWSR1 to FLI1 is sufficient to recapitulate BAF complex retargeting and EWS-FLI1 activities. Our studies thus demonstrate that the physical properties of prion-like domains can retarget critical chromatin regulatory complexes to establish and maintain oncogenic gene expression programs. Citation Format: Gaylor Boulay, Gabriel J. Sandoval, Nicolo Riggi, Sowmya Iyer, Rémi Buisson, Beverly Naigles, Mary E. Awad, Shruthi Rengarajan, Angela Volorio, Matthew J. McBride, Liliane C. Broye, Lee Zou, Ivan Stamenkovic, Cigall Kadoch, Miguel N. Rivera. Cancer-specific retargeting of BAF complexes by a prion-like domain [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr PR09.