Title:The Role of B Cell Receptor Stimulation in CLL Pathogenesis
Volume: 18
Issue: 23
Author(s): Laurens P. Kil, Saravanan Yuvaraj, Anton W. Langerak and Rudi W. Hendriks
Affiliation:
Keywords:
B cell receptor, Bruton’s tyrosine kinase, chronic lymphocytic leukemia, IGHV mutation status, antigen-experienced cells, antigenic pressure, autoantigens, CLL leukemogenesis, tyrosine kinase, cytopenia
Abstract: Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in adults in the Western world and is characterized by the
accumulation of monoclonal CD5+ mature B cells in the blood. The disease has a highly variable clinical course. CLL is subdivided into
two disease subtypes, whereby leukemias with hypermutated immunoglobulin heavy chain variable (IGHV) genes have a more favorable
prognosis than those with unmutated IGHV genes, which tend to show advanced, progressive disease, adverse cytogenetic features and
resistance to therapy. The current view is that both CLL types derive from antigen-experienced cells. Based on the finding that the IGHV
repertoire is highly restricted and biased, as compared to the normal adult B-cell repertoire, it has been hypothesized that CLL cells are
selected by some sort of antigenic pressure. Hereby, either autoantigens or antigens derived from apoptotic cells or pathogens are essential
to trigger CLL pathogenesis. Although different cytogenetic aberrations were shown to contribute to CLL leukemogenesis, it remains
unclear which abnormalities are primary events. Very recently, whole-genome sequencing identified genes that are recurrently mutated
and provided novel insights into the mechanisms of oncogenic transformation. Because of the impact on prognosis, it is important to unravel
the role of antigenic selection in CLL. Interestingly, B cell receptor (BCR) signaling is aberrantly increased in CLL and expression
of tyrosine kinase ZAP70, which is able to signal downstream of the BCR, is a prognostic indicator. In this context we discuss the functional
significance of antigenic selection in CLL and describe emerging agents to target BCR signaling that are currently being tested as a
novel therapeutic strategy for CLL.
