BRG1 promotes progression of B-cell acute lymphoblastic leukemia by disrupting PPP2R1A transcription

Despite advancements in chemotherapy and the development of novel therapies, outcomes for adult patients with B-cell acute lymphoblastic leukemia (B-ALL) remain poor. A better understanding of the molecular mechanisms driving B-ALL progression is therefore essential. Brahma-related gene 1 (BRG1), previously identified as a negative prognostic factor in various cancers, was found to be significantly overexpressed in B-ALL patients—regardless of molecular subtype—compared to healthy individuals, and its elevated expression correlated with worse prognosis.

Functionally, BRG1 overexpression promoted B-ALL cell proliferation by accelerating cell cycle progression into the S phase, while its knockdown induced apoptosis. Mechanistic analysis revealed that BRG1 binds to the transcriptional activation region of PPP2R1A, suppressing its expression and activating the PI3K/AKT signaling pathway, thereby upregulating proto-oncogenes c-Myc and BCL-2. Importantly, both BRG1 silencing and treatment with PFI-3—a specific BRG1 inhibitor—significantly suppressed leukemia progression and extended survival in B-ALL cell-derived xenograft mouse models.

Conclusion: BRG1 promotes B-ALL progression through repression of PPP2R1A and activation of the PI3K/AKT pathway. Targeting BRG1 offers a promising therapeutic approach for adult B-ALL.