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

Mutant SMARCA4 in T-cell acute lymphoblastic leukemia cell lines confers resistance to a broad range of chemotherapeutic agents by disrupting AP-1-associated chromatin remodeling.

• Why it matters: SMARCA4 mutations are rare at diagnosis but enriched in relapse, implying a therapy-resistance mechanism that depends on how chromatin remodelers shape drug responses.
• What they did: The study used isogenic T-ALL cell lines with or without SMARCA4 mutations, then combined ATAC-seq and RNA-seq to assess chemotherapy-linked transcription and remodeling at AP-1 regulatory regions.
• The result: SMARCA4-mutant cells showed an attenuated transcriptional response to chemotherapy, with impaired AP-1-associated remodeling, downregulated stress-related genes, and preserved cellular fitness programs; AP-1 inhibition phenocopied this pattern.

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