ARID1A and ARID1B safeguard B cell identity, prevent myeloid transformation and expose therapeutic vulnerabilities in lymphoma

Chromatin remodeling by the SWI/SNF complex is essential for hematopoietic lineage commitment and differentiation. While core subunits ARID1A and ARID1B are frequently mutated in B cell malignancies, their functions remain unclear. Recent work established ARID1A- dependent functions within germinal center (GC) B cells, but its role during early B cell development, and whether its homolog, ARID1B, contributes distinct or compensatory roles at steady state or during transformation, remain unknown. Here, we used CD19-Cre-mediated deletion initiated at the pro-B cell stage to investigate their role in B cell development in vivo. Loss of either gene partially blocked B cell differentiation, reducing immature/recirculating B cell output, and impaired germinal center formation following antigen challenge. Combined deletion further reduced peripheral B cells, shortened survival, and resulted in aggressive leukemia. Unexpectedly, the malignancy was of myeloid origin and arose from a subset of CD19-expressing multipotent progenitors (MPPs). Arid1a/Arid1b-deficient MPPs exhibited abnormal expansion, reduced colony formation, and dysregulation of stemness and lineage-priming programs, including diminished CBFA2T3 (ETO2) and Fli1 signatures. In established B cell lymphoma cells in vitro, double ARID1A/ARID1B loss modestly affected cell growth, whereas loss of ARID1A increased sensitivity to EZH2 inhibition. Transcriptomic analyses revealed alterations in cell adhesion/migration pathways, cytokine-receptor interactions and DNA repair mechanisms. Collectively, these findings reveal stage-specific and compensatory roles for ARID1A and ARID1B in B cell development, uncover a mechanism by which SWI/SNF loss in MPPs redirects transformation towards myeloid leukemia, and suggest context-dependent therapeutic vulnerabilities.