Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling

MD Minden, R Übelhart, D Schneider, T Wossning… - Nature, 2012 - nature.com
MD Minden, R Übelhart, D Schneider, T Wossning, MP Bach, M Buchner, D Hofmann…
Nature, 2012nature.com
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 …
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.
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