SMARCA4 MUTATIONS PROMOTE CHEMOTHERAPY RESISTANCE IN T-ACUTE LYMPHOBLASTIC LEUKEMIA THROUGH ALTERED CHROMATIN REMODELING AT AP1-ASSOCIATED REGULATORY REGIONS

Abstract

Chromatin remodelers play a critical role in orchestrating chemotherapy responses in cancer cells. Components of the SWI/SNF complex are frequently mutated across cancer types, with the ATPase subunit SMARCA4 among the most commonly altered. In T-cell acute lymphoblastic leukemia (T-ALL), however, SMARCA4 mutations are rare at diagnosis but enriched in relapse samples, suggesting a potential role in therapy resistance. Using isogenic T-ALL cell lines with or without SMARCA4 mutations, we show that mutant SMARCA4 confers resistance to a broad range of chemotherapeutic agents. By combining ATAC-seq and RNA-seq, we demonstrate that SMARCA4-mutant cells display an attenuated transcriptional response to chemotherapy accompanied by impaired remodeling of AP-1-associated regulatory regions linked to stress response. These cells downregulate stress-related genes while maintaining expression programs associated with cellular fitness. Pharmacological inhibition of AP-1 phenocopies this response, further supporting a functional link between SWI/SNF-mediated remodeling at AP-1-associated regulatory regions, AP-1 activity, and chemotherapy sensitivity. Together, our findings indicate that SWI/SNF-mediated remodeling of these regions contributes to an effective chemotherapy-induced stress response, and that its failure provides T-ALL cells with a survival