Abstract A020: A SMARCA1/SMARCA5 double-knockout-repressed ISWI chromatin-state program marks fusion-enriched pediatric sarcoma models and an ISWI-complex dependency signal in rhabdomyosarcoma
TL;DR
The relationship between DKOdown and multiple chromatin-remodeling family programs supports a model in which coordinated chromatin-remodeler activity may contribute to lineage dysregulation, adaptive plasticity, and ISWI-associated vulnerability in rhabdomyosarcoma and related fusion-enriched sarcoma models.
Abstract
Cell-state plasticity has been linked to lineage dysregulation, therapeutic adaptation, and tumor persistence in pediatric and fusion-driven sarcomas, but the chromatin-remodeling programs associated with these states remain incompletely defined. Building on prior SMARCA1/SMARCA5 perturbation work in rhabdomyosarcoma, this study tested whether a human ortholog-mapped ISWI signature repressed after SMARCA1/SMARCA5 double knockout (DKO) could identify related chromatin-state patterns across public sarcoma models. DepMap sarcoma models were grouped by histology, including rhabdomyosarcoma, Ewing sarcoma, synovial sarcoma, osteosarcoma, malignant peripheral nerve sheath tumor, leiomyosarcoma, undifferentiated pleomorphic sarcoma, liposarcoma, fibrosarcoma, and other sarcoma. The DKO-repressed ISWI program, referred to as DKOdown, was scored from gene expression after mapping source DKO-repressed genes to human orthologs. DKOdown distributions were compared across sarcoma groups, fusion-driven or fusion-enriched versus non-fusion or complex-karyotype classes, and pediatric/AYA-enriched versus other/adult-predominant classes. DKOdown was also assessed against core ISWI, BAF, NuRD, and ncBAF expression programs and DepMap CRISPR gene-effect profiles for chromatin-remodeling genes. DKOdown showed the highest median score in rhabdomyosarcoma and was also elevated in synovial sarcoma and Ewing sarcoma. DKOdown was higher in fusion-driven or fusion-enriched models than in non-fusion or complex-karyotype models, with a median difference of 0.227, Wilcoxon p = 6.6e-6, and FDR = 3.69e-5. DKOdown was also higher in pediatric/AYA-enriched sarcoma models than in other/adult-predominant sarcoma models, with a median difference of 0.172, Wilcoxon p = 4.11e-5, and FDR = 7.86e-4. Across sarcoma models, DKOdown positively correlated with core ISWI, BAF, NuRD, and ncBAF expression programs, consistent with a broader chromatin-remodeler-associated transcriptional state. Functional annotation highlighted developmental, chromatin-regulatory, and tissue-remodeling terms, linking DKOdown to a chromatin-state pattern relevant to sarcoma plasticity. Rhabdomyosarcoma models also showed a stronger mean ISWI-complex dependency signal, suggesting a potential ISWI-linked vulnerability. This DepMap-based analysis identifies a human ortholog-mapped SMARCA1/SMARCA5 DKO-repressed ISWI program as a candidate marker of fusion-enriched and pediatric/AYA-associated sarcoma cell states. The relationship between DKOdown and multiple chromatin-remodeling family programs supports a model in which coordinated chromatin-remodeler activity may contribute to lineage dysregulation, adaptive plasticity, and ISWI-associated vulnerability in rhabdomyosarcoma and related fusion-enriched sarcoma models. Experimental validation will be needed to determine whether DKOdown functionally regulates plasticity, differentiation blockade, or therapy response. Generative AI was used only for language editing. Ashwaq K. Aljabri. A SMARCA1/SMARCA5 double-knockout-repressed ISWI chromatin-state program marks fusion-enriched pediatric sarcoma models and an ISWI-complex dependency signal in rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Bridging Discovery and Clinical Impact in Pediatric Cancer; 2026 Sep 22-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_1):Abstract nr A020.
