ARID1A and ARID1B preserve B cell identity, prevent myeloid transformation and reveal therapeutic vulnerabilities
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 specific roles in B cell development and transformation remain poorly understood. Here, we investigated the function of these SWI/SNF components using conditional knockout mice with CD19-Cre–mediated deletion, initiated at the pro-B cell stage. Loss of either Arid1a or Arid1b led to a partial block in B cell differentiation in the bone marrow and impaired germinal center formation following antigen exposure.  Double deletion of Arid1a and Arid1b resulted in a more severe phenotype, with marked reduction in peripheral B cells, shortened overall survival, and development of an aggressive leukemia. Surprisingly, the malignancy was of myeloid origin, arising from a small subset of CD19-expressing multipotent progenitors (MPPs). These Arid1a/Arid1b-deficient MPPs exhibited abnormal expansion, defective differentiation in methylcellulose assays, and transcriptional dysregulation of key self-renewal programs driven by CBFA2T3 (ETO2) and Fli1.  In established B cell lymphoma cells in vitro, loss of ARID1A and ARID1B together mildly affected cell growth, while loss of ARID1A increased sensitivity to pharmacological EZH2 inhibition. Collectively, our findings reveal stage-specific and compensatory roles for ARID1A and ARID1B in B cell development, uncover a previously unrecognized mechanism by which SWI/SNF loss in early progenitors can drive transformation towards myeloid leukemia, and identified possible therapeutic vulnerabilities in patients with ARID1A mutations. Overall design: RNA sequencing performed on SUDHL6 cells targeted using CRISPR/Cas9 to inactivate expression of ARID1A, ARID1B or both.  Non-target sgRNA used to generate stable control cell line clones.  Mouse primary multipotent progenitors (MPPs) were harvested from bone marrow, sorted using FACS, and processed for RNA isolation right after.