The importance of B cell receptor isotypes and stereotypes in chronic lymphocytic leukemia.
B cell receptor (BCR) signaling is a central pathway promoting the survival and proliferation of normal and malignant B cells. Chronic lymphocytic leukemia (CLL) arises from mature B cells, expressing functional BCRs, mainly of immunoglobulin M (IgM) and IgD isotypes. Importantly, 30% of CLL patients express quasi-identical BCRs, the so-called "stereotyped" receptors, indicating the existence of common antigenic determinants, which may drive disease initiation and favor its progression. Although the antigenic specificity of IgM and IgD receptors is identical, there are distinct isotype-specific responses after IgM and IgD triggering. Here, we discuss the most important steps of normal B cell development, and highlight the importance of BCR signaling for CLL pathogenesis, with a focus on differences between IgM and IgD isotype signaling. We also highlight the main characteristics of CLL patient subsets, based on BCR stereotypy, and describe subset-specific BCR function and antigen-binding characteristics. Finally, we outline the key biologic and clinical responses to kinase inhibitor therapy, targeting the BCR-associated Bruton's tyrosine kinase, phosphoinositide-3-kinase, and spleen tyrosine kinase in patients with CLL.