B cell receptor in MBL

The central role of the B cell receptor (BcR) in the development of chronic lymphocytic leukemia (CLL) is widely acknowledged. However, understanding its precise significance in the early stages of CLL, such as monoclonal B cell lymphocytosis (MBL), remains a challenge. In this study, we conducted a thorough examination of the BcR in both low-count (LC-MBL, n=16) and high-count MBL (HC-MBL, n=14) cases, comparing them to CLL. HC-MBL closely resembled CLL at the immunogenetic level, displaying a more clonal profile and greater intraclonal diversification within the immunoglobulin (IG) genes compared to LC-MBL. LC-MBL, on the other hand, often exhibited oligoclonal characteristics with limited intraclonal diversification and fewer stereotyped BcR IG patterns. Transcriptomic analysis distinguished CLL from both HC-MBL and LC-MBL. While CLL showed upregulation in pathways such as Notch, p53, and BcR, HC-MBL and LC-MBL exhibited gene expression signatures associated with chronic inflammation and primary immunodeficiency, respectively. LC-MBL also demonstrated downregulation of pathways including BcR, FoxO, VEGF, and Wnt signaling compared to CLL. Moreover, recombinant monoclonal antibodies from MBL cases displayed weaker reactivity against a wide range of autoantigens and pathogens compared to CLL, which exhibited stronger recognition of a more limited set of antigens. Additionally, we found evidence of antigen-independent autonomous BcR signaling in MBL, even in LC-MBL cases. In summary, our study highlights significant differences in BcR structure and function between MBL, particularly the LC-MBL subtype, and CLL. These disparities suggest distinct antigen exposure histories and maturation processes, underscoring the unique nature of LC-MBL in comparison to CLL.