Abstract P11: ARID1A mutations shape memory B-cell dynamics and confer sensitivity to SWI/SNF remodeling complex inhibition in lymphoma
Authors: Barisic Darko , Chin Christopher R. , Meydan Cem , Teater Matt , Tsialta Ioanna , Mlynarczyk Coraline , Steidl Christian , Scott David W. , Weng Andrew P. , Green Michael R. , Melnick Ari 
Published: March 2024

Abstract
Mutations in the mammalian SWI/SNF chromatin remodeling complex, particularly in the ARID1A subunit, are commonly found in various cancers, with a high prevalence in lymphoma (&gt;35%). However, the precise mechanisms by which ARID1A mutations lead to lymphoma remain unknown. We developed a mouse model with ARID1A deletion specifically in germinal center B cells, FL and DLBCL cell-of-origin. We found that ARID1A deletion results in fewer germinal centers and disrupted the progression of the B-cell transcriptional program, causing widespread chromatin repression, decreased nucleosome turnover, and increased nucleosome density at transcription factor binding sites leading to reduced PU.1 and NF-kB binding. Loss of these factors occurred at genes involved in cytokine and CD40 signaling, indicating premature germinal center exit. We therefore determined the levels of post-germinal center populations and observed an increase of memory B cells, especially the CD80−PDL2− subset, which are more likely to return to germinal centers upon antigen recall rather than differentiating into plasma cells. Similarly, we observed a decrease in long-lived plasma cells, indicating that ARID1A deletion drives the germinal center exit towards the reactive memory B cells, potential precursors to lymphoma. To further support our findings, we used an adoptive transfer where ARID1A-deficient antigen-specific memory B cells were transferred into recipient mice lacking mature B cells (μMT). Upon re-immunization, these ARID1A-deficient cells were more likely to contribute to new germinal centers compared to WT cells (2-fold enrichment), supporting the notion that ARID1A loss leads to an increased pool of memory B cells prone to recall, likely contributing to lymphoma precursor pools. Investigating the implications for lymphoma, we found that mice with ARID1A mutations had shortened survival, and lymphoma patients with these mutations had a memory B-cell-like phenotype with a higher risk of transforming to aggressive forms of the disease. These findings offer mechanistic understanding into the emergence of aggressive lymphomas in ARID1A-mutant patients. Next, we aimed to explore therapeutic vulnerabilities to target these aggressive ARID1A-mutated lymphoma cells. Considering the reliance of ARID1A-mutant lymphoma cells on remaining SWI/SNF complex functions, we targeted these cells with FHD-286, a potent SMARCA4/2 inhibitor currently in clinical trials for other tumors. The treatment selectively eliminated ARID1A-mutant cells while not impacting WT cells. These effects were confirmed using an alternative SMARCA4/2 degrader, with apoptosis occurring at higher rates in ARID1A-mutant cells. Finally, in vivo trials using xenografts from isogenic lymphoma cell lines demonstrated that FHD-286 was significantly more effective against ARID1A-mutant lymphomas, leading to tumor regression and increased survival. These results underline the vulnerability of ARID1A mutant lymphomas to SMARCA4/2 inhibition and the potential for new treatments of SWI/SNF-deficient B-cell lymphomas.
Citation Format: Darko Barisic, Christopher R. Chin, Cem Meydan, Matt Teater, Ioanna Tsialta, Coraline Mlynarczyk, Christian Steidl, David W. Scott, Andrew P. Weng, Michael R. Green, Ari Melnick. ARID1A mutations shape memory B-cell dynamics and confer sensitivity to SWI/SNF remodeling complex inhibition in lymphoma [abstract]. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P11.