Barisic, D., Chin, C. R., Meydan, C., Teater, M., Tsialta, I., Mlynarczyk, C., Chadburn, A., Wang, X., Sarkozy, M., Xia, M., Carson, S. E., Raggiri, S., Debek, S., Pelzer, B., Durmaz, C., Deng, Q., Lakra, P., Rivas, M., Steidl, C., Scott, D. W., Weng, A. P., Mason, C. E., Green, M. R., Melnick, A. (2024). ARID1A orchestrates SWI/SNF-mediated sequential binding of transcriptional factors with ARID1A loss driving pre-memory B cell fate and lymphomagenesis. Cancer Cell. https://doi.org/10.1016/j.ccell.2024.02.010
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.
Journal: Cancer Cell PMID: N/A DOI: 10.1016/j.ccell.2024.02.010
https://doi.org/10.1016/j.ccell.2024.02.010