Transcriptional reprogramming in mantle cell lymphoma promotes BTK inhibitor resistance

Resistance to Bruton’s tyrosine kinase inhibitors (BTKi) remains a major therapeutic challenge in B-cell malignancies, limiting treatment durability. We demonstrate BRG1-mediated chromatin remodeling as a major driver of BTKi resistance. We show that cancer-associated BRG1 ATPase domain mutations protect cells from BTKi-induced ferroptosis by limiting reactive oxygen species (ROS) production and labile iron. Mechanistically, the BRG1T910M mutation activates the unfolded protein response (UPR) via ATF4, leading to upregulation of MEF2B, a key suppressor of ferroptosis. MEF2B further inhibits mitochondrial respiration and thus prevent BTKi-induced mitophagy and ferroptosis. Pharmacological inhibition of BRG1 promotes ferroptosis by suppressing pro-survival B cell receptor (BCR) signaling and the ATF4-MEF2B axis. We show that a clinical stage BRG1 inhibitor restores ferroptosis in BTKi-resistant cells and synergizes with BTKi across various MCL models. Together we propose for co-targeting BRG1 and BTK in treatment of B-cell malignancies. MINO cells expressing wildtype or mutant BRG1 or treated with FHD-286 were analyzed by RNA-seq. JEKO cells ectopically expressing MEF2B were analyzed by RNA-seq. Primary MCL cells were analyzed by RNA-seq. MINO cells expressing wildtype or mutant SMARCA4 or treated with FHD-286 were analyzed by ATAC-seq or BRG1/H2K27Ac Cut&Run. CCMCL1 cells expressing cas9-sgROSA or cas9-sgBRG1 were analyzed by ATAC-seq. JEKO cells ectopically expressing MEF2B were analyzed by Cut&Run.