Insights into the pathogenesis and biology of chronic lymphocytic leukemia through analysis of its B-cell receptor

The B-cell antigen receptor (BCR) plays an essential role in the pathogenesis of B-cell malignancies such as chronic lymphocytic leukemia (CLL). CLL exhibits two main subtypes based on immunoglobulin heavy chain variable (IGHV) region mutational status: About half of the cases carry somatically mutated immunoglobulin V genes and hence derive from germinal center experienced memory B cells, whereas unmutated CLL derives from (likely CD5-positive) antigen-stimulated, but germinal center independent mature B cells. CLL precursor cells can be found years before diagnosis. The IGHV mutational status of CLL clones serves as one of the strongest prognostic markers. CLL often carries highly similar, i.e. stereotyped BCRs pointing to recognition of a restricted set of antigens. Indeed, the BCRs of many CLL clones are autoreactive for particular autoantigens, including the BCR itself. Pathogenic antigens are further drivers in CLL development. Thus, BCR-mediated signaling and antigen recognition play a major role in CLL pathogenesis.