Abstract Objective: Soft tissue sarcomas (STS) are rare in both pediatric and adult cancer patients, yet they remain highly lethal and understudied. Many STS subtypes, including undifferentiated pleomorphic sarcoma (UPS) and embryonal rhabdomyosarcoma (eRMS), exhibit significant genetic heterogeneity and lack recurrent oncogenic driver mutations, complicating the development of broadly effective therapies. A promising strategy is to design targeted treatments for subsets of STS driven by specific tumor suppressor alterations. However, the molecular pathogenesis of UPS and eRMS remains poorly understood, limiting therapeutic progress. Germline and somatic mutations in BRCA1-associated protein 1 (BAP1), an epigenetic regulator, have been linked to multiple STS subtypes, yet its role in suppressing sarcoma development is unclear. Using a murine model, we recently identified BAP1 deletion as a driver event in STS development. This model provides a platform to dissect BAP1’s functional role and to explore novel therapeutic strategies. Methods: We established well-characterized Bap1-deficient sarcoma cell lines derived from mouse models of STS driven by somatic deletion of Bap1 and Trp53. A high-throughput epigenetic inhibitor screen using the CellCyte proliferation assay was performed to identify the most effective inhibitors. Additional approaches included syngeneic and primary sarcoma mouse models, CRISPR/Cas genetic tools, flow cytometry, multiplex immunohistochemistry (IHC), single-cell RNA sequencing, and bulk RNA sequencing to evaluate the impact of epigenetic inhibitors on Bap1-driven STS and its immune-suppressive microenvironment. Results: Bap1-deficient sarcoma cells exhibited marked sensitivity to several potent epigenetic inhibitors, including histone deacetylase inhibitors (HDACi), bromodomain and extra-terminal domain inhibitors (BETi), and histone demethylase inhibitors. Studies assessing their effects on the immune-suppressive microenvironment are ongoing. Conclusion: Our findings establish Bap1 deficiency as a driver of STS development and reveal that Bap1-deficient sarcomas are highly susceptible to epigenetic inhibition. These results lay the foundation for translating epigenetic therapies into effective treatment strategies for patients with Bap1-driven STS, a population currently lacking targeted options. Citation Format: Xingliang Liu, William Haugh, Bryan R. Bell, Jianguo Huang. Bap1 driven soft tissue sarcomas: Mouse modeling and therapeutic strategies abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 613.
Liu et al. (Fri,) studied this question.