SWI/SNF Chromatin Remodeling Complex Orchestrates Sequential Binding of Key Transcription Factors in B Cells and Restricts Aggressive Lymphoma [human CUT&RUN]
ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. Our study shows that ARID1A orchestrates B-cell fate during the germinal center (GC) response, facilitating cooperative and sequential binding of PU.1 and NF-kB at crucial genes for cytokine and CD signaling. The absence of ARID1A tilts GC cell-fate towards immature IgM+CD80-PDL2- memory B-cells, known for their potential to re-enter new GCs. When combined with BCL2 oncogene, ARID1A haploinsufficiency hastens the progression of aggressive follicular lymphomas in mice. Remarkably, follicular lymphoma patients with ARID1A-inactivating mutations preferentially display an immature memory B-cell-like state with increased transformation risk to aggressive disease. These observations offer mechanistic understanding into the emergence of both indolent and aggressive lymphomas in ARID1A-mutant patients through formation of immature memory-like clonal precursors. Lastly, we demonstrate that ARID1A mutation induces synthetic lethality to SMARCA2/4 inhibition, paving the way for potential precision therapy for high-risk patients. Overall design: CUT&RUN was performed using Epicypher protocol with a light fixation protocol (1min 0.1% PFA). Antibodies used; ARID1A (1235S), IgG (ABIN101961), BRD9 (137245), PU.1 (2266S), H3.3 (91191), H3K27me3 (13027S). Two genotypes were used; ARID1A WT and HET. All experiments were done in RIVA cell line.