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
Ashwaq K. AljabriAbstract
Introduction:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
Citation Format:
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.