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.
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
Current Pharmaceutical Design
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.
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Cite this article as:
P. Kil Laurens, Yuvaraj Saravanan, W. Langerak Anton and W. Hendriks Rudi, The Role of B Cell Receptor Stimulation in CLL Pathogenesis, Current Pharmaceutical Design 2012; 18 (23) . https://dx.doi.org/10.2174/138161212801227041
DOI https://dx.doi.org/10.2174/138161212801227041 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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