The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma

Matthew J McBride; John L Pulice; Hannah C Beird; Davis R Ingram; Andrew R D'Avino; Jack F Shern; Gregory W Charville; Jason L Hornick; Robert T Nakayama; Enrique M Garcia-Rivera; Dejka M Araujo; Wei-Lien Wang; Jen-Wei Tsai; Michelle Yeagley; Andrew J Wagner; P Andrew Futreal; Javed Khan; Alexander J Lazar; Cigall Kadoch

doi:10.1016/j.ccell.2018.05.002

The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma

Cancer Cell. 2018 Jun 11;33(6):1128-1141.e7. doi: 10.1016/j.ccell.2018.05.002. Epub 2018 May 31.

Authors

Matthew J McBride¹, John L Pulice², Hannah C Beird³, Davis R Ingram⁴, Andrew R D'Avino², Jack F Shern⁵, Gregory W Charville⁶, Jason L Hornick⁷, Robert T Nakayama⁸, Enrique M Garcia-Rivera², Dejka M Araujo⁹, Wei-Lien Wang⁴, Jen-Wei Tsai⁴, Michelle Yeagley⁹, Andrew J Wagner¹⁰, P Andrew Futreal³, Javed Khan⁵, Alexander J Lazar¹¹, Cigall Kadoch¹²

Affiliations

¹ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Epigenomics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Chemical Biology, Harvard University, Cambridge, MA, USA.
² Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Epigenomics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX, USA.
⁴ Department of Pathology, MD Anderson Cancer Center, Houston, TX, USA; Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX, USA.
⁵ Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA.
⁶ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
⁷ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Ludwig Center at Dana-Farber/Harvard and Center for Sarcoma and Bone Oncology, Department of Medical Oncology, Harvard Medical School, Boston, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
⁹ Department of Sarcoma Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
¹⁰ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
¹¹ Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX, USA; Department of Pathology, MD Anderson Cancer Center, Houston, TX, USA; Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX, USA.
¹² Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Epigenomics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: [email protected].

Abstract

Synovial sarcoma (SS) is defined by the hallmark SS18-SSX fusion oncoprotein, which renders BAF complexes aberrant in two manners: gain of SSX to the SS18 subunit and concomitant loss of BAF47 subunit assembly. Here we demonstrate that SS18-SSX globally hijacks BAF complexes on chromatin to activate an SS transcriptional signature that we define using primary tumors and cell lines. Specifically, SS18-SSX retargets BAF complexes from enhancers to broad polycomb domains to oppose PRC2-mediated repression and activate bivalent genes. Upon suppression of SS18-SSX, reassembly of BAF47 restores enhancer activation, but is not required for proliferative arrest. These results establish a global hijacking mechanism for SS18-SSX on chromatin, and define the distinct contributions of two concurrent BAF complex perturbations.

Keywords: ATP-dependent chromatin remodeling; SWI/SNF (BAF) complexes; bivalency; chromatin; enhancers; fusion oncoprotein; pediatric cancer; polycomb; synovial sarcoma.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Chromatin / genetics*
Chromatin / metabolism
Enhancer Elements, Genetic / genetics
Exome Sequencing / methods
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques / methods
HEK293 Cells
Humans
Oncogene Proteins, Fusion / genetics*
Oncogene Proteins, Fusion / metabolism
SMARCB1 Protein / genetics*
SMARCB1 Protein / metabolism
Sarcoma, Synovial / genetics*
Sarcoma, Synovial / metabolism
Sarcoma, Synovial / pathology

Substances

Chromatin
Oncogene Proteins, Fusion
SMARCB1 Protein
SS18-SSX1 fusion protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding