VPREB1 encodes a component of the surrogate light chain that associates with the immunoglobulin heavy chain to form the pre-B cell receptor (pre-BCR) complex, which is essential for early B cell development 1. The gene exhibits developmental stage-specific expression, with low levels in pro-B cells, high levels in pre-BI cells, and slightly lower levels in pre-BII cells, before being downregulated in immature/mature B cells 1. The pre-BCR complex serves as a critical checkpoint during bone marrow B cell development, and failure of pre-BCR signaling is proposed as a critical factor for B-cell acute lymphoblastic leukemia (B-ALL) development 2. VPREB1 mutations and deletions have been identified in various B cell malignancies, including B-ALL and multiple myeloma, where CRISPR-mediated knockout of VPREB1 demonstrated cytotoxic effects on myeloma cell proliferation 3. Copy number variations in VPREB1 show significant disease associations: fewer than 2 copies are associated with increased rheumatoid arthritis risk, while more than 2 copies appear protective 45. Additionally, VPREB1 deletion has been identified as a predictor of relapse in Philadelphia chr22-positive ALL patients treated with targeted therapy 6. Mutations in VPREB1 can also cause autosomal recessive agammaglobulinemia, characterized by absent peripheral B cells and severe hypogammaglobulinemia 7.