SRP486855 PRJNA1071095 GSE254588 SWI/SNF Chromatin Remodeling Complex Orchestrates Sequential Binding of Key Transcription Factors in B Cells and Restricts Aggressive Lymphoma [human ATAC-Seq] 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: ATAC-seq was performed as per Omni-ATAC-seq protocol, on three biological replicates for each condition. WT and HET (for Arid1a) were processed in a separate experiment compared to sh-knockdown. Therefore, sh-uninduced control was added (KD and sh-control). Sh-experiment was perfomred with two different sh-constructs targeting Arid1a, each with two biological replicates. GSE254588 pubmed 38458187 parent_bioproject PRJNA997344