Arid1a and Arid1b maintain B cell lineage fidelity and constrain myeloid transformation in mice.

Chromatin remodeling by mammalian SWI/SNF complexes is essential for hematopoietic lineage specification and differentiation. Although the canonical BAF subunits ARID1A and ARID1B are recurrently altered in B-cell malignancies, their overlapping and stage-specific functions during B-cell development remain incompletely understood. Here, we used CD19-Cre-mediated deletion of Arid1a and Arid1b to define their roles in B-cell development and hematopoietic transformation in vivo. Loss of either Arid1a or Arid1b impaired B-cell differentiation, reduced immature and recirculating B-cell output, and compromised germinal center responses following antigen challenge, with more pronounced defects following combined deletion. Unexpectedly, combined Arid1a/Arid1b loss resulted in a lethal, transplantable myeloid leukemia rather than a B-cell malignancy. CD19-Cre lineage tracing and allele-recombination analysis identified a subset of multipotent progenitors carrying CD19-Cre activity, while combined deletion was associated with selective MPP3 expansion and impaired myelo-erythroid colony-forming capacity. Transcriptional profiling of Arid1a/Arid1b-deficient MPP2/3 cells revealed loss of HSPC- and lymphoid-associated programs together with aberrant activation of erythroid and megakaryocyte-erythroid transcriptional states, without acquisition of a conventional mature myeloid program. These findings reveal overlapping functions of ARID1A and ARID1B in B-cell development and support a broader role for canonical BAF complexes in maintaining hematopoietic lineage fidelity and constraining malignant transformation.