ARID1A orchestrates SWI/SNF-mediated sequential binding of transcription factors with ARID1A loss driving pre-memory B cell fate and lymphomagenesis

Cancer Cell. 2024 Apr 8;42(4):583-604.e11. doi: 10.1016/j.ccell.2024.02.010. Epub 2024 Mar 7.


ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. We show 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 CD40 signaling. The absence of ARID1A tilts GC cell fate toward immature IgM+CD80-PD-L2- 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 (FLs) in mice. Patients with FL 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 ARID1A-mutant lymphomas through the 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.

Keywords: BAF complex; chromatin; chromatin remodeling; clonal precursor cells; epigenetics; humoral immunity; lymphoma; pioneer transcription factors; plasticity; precision therapy.

MeSH terms

  • Animals
  • DNA-Binding Proteins / genetics
  • Humans
  • Lymphoma* / genetics
  • Memory B Cells*
  • Mice
  • Mutation
  • Nuclear Proteins / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • ARID1A protein, human
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Transcription Factors
  • Arid1a protein, mouse