1. Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling.
- Author
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Minden, Marcus Dühren-von, Übelhart, Rudolf, Schneider, Dunja, Wossning, Thomas, Bach, Martina P., Buchner, Maike, Hofmann, Daniel, Surova, Elena, Follo, Marie, Köhler, Fabian, Wardemann, Hedda, Zirlik, Katja, Veelken, Hendrik, and Jumaa, Hassan
- Subjects
LYMPHOCYTIC leukemia ,B cells ,ANTIGEN receptors ,EPITOPES ,CARCINOGENESIS ,WESTERN countries - Abstract
B-cell antigen receptor (BCR) expression is an important feature of chronic lymphocytic leukaemia (CLL), one of the most prevalent B-cell neoplasias in Western countries. The presence of stereotyped and quasi-identical BCRs in different CLL patients suggests that recognition of specific antigens might drive CLL pathogenesis. Here we show that, in contrast to other B-cell neoplasias, CLL-derived BCRs induce antigen-independent cell-autonomous signalling, which is dependent on the heavy-chain complementarity-determining region (HCDR3) and an internal epitope of the BCR. Indeed, transferring the HCDR3 of a CLL-derived BCR provides autonomous signalling capacity to a non-autonomously active BCR, whereas mutations in the internal epitope abolish this capacity. Because BCR expression was required for the binding of secreted CLL-derived BCRs to target cells, and mutations in the internal epitope reduced this binding, our results indicate a new model for CLL pathogenesis, with cell-autonomous antigen-independent signalling as a crucial pathogenic mechanism. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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