A role for SMARCB1 in synovial sarcomagenesis reveals that SS18-SSX induces canonical BAF destruction.

Reduced protein levels of SMARCB1 (a.k.a. BAF47, INI1, SNF5) have long been observed in synovial sarcoma (SS). Here, we show that combined Smarcb1 genetic loss with SS18-SSX expression in mice synergized to produce aggressive tumors with histomorphology, transcriptomes, and genome-wide BAF-family complex distributions distinct from SS18-SSX alone, indicating a defining role for SMARCB1 in SS. Smarcb1 silencing alone in mesenchyme modeled epithelioid sarcomagenesis. In mouse and human SS cells, SMARCB1 was identified within PBAF and canonical BAF (CBAF) complexes, co-incorporated with SS18-SSX in the latter. Recombinant expression of CBAF components in human cells reconstituted CBAF sub-complexes that contained equal levels of SMARCB1, regardless of SS18 or SS18-SSX inclusion. In vivo, SS18-SSX expression led to whole-complex CBAF degradation, rendering increases in the relative prevalence of other BAF-family subtypes, PBAF and GBAF complexes, over time. Thus, SS18-SSX alters BAF subtypes levels/balance and genome distribution, driving synovial sarcomagenesis.