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 lineage-specific functions remain unclear. Here, we used CD19-Cre-mediated conditional deletion initiated at the pro B cells stage to investigate the function of Arid1a/1b in vivo in mice. Loss of either gene partially blocked B cell differentiation in the bone marrow, reducing immature/recirculating B cell output, and impaired germinal center formation following antigen challenge. Combined deletion resulted in a more severe phenotype, with marked reduction in peripheral B cells, shortened survival, and development of an aggressive leukemia. Unexpectedly, the malignancy was of myeloid origin and arose from a small subset of CD19-expressing multipotent progenitors (MPPs). Arid1a/Arid1b-deficient MPPs exhibited abnormal expansion, reduced colony formation in methylcellulose, and transcriptional 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 only modestly affected cell growth, whereas loss of ARID1A increased sensitivity to pharmacological EZH2 inhibition. Transcriptomic analysis revealed major 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 early progenitors can drive transformation towards myeloid leukemia, and suggests context-dependent therapeutic vulnerabilities.