Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling.
Nature
; 489(7415): 309-12, 2012 Sep 13.
Article
in En
| MEDLINE
| ID: mdl-22885698
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.
Full text:
1
Database:
MEDLINE
Main subject:
Receptors, Antigen, B-Cell
/
Leukemia, Lymphocytic, Chronic, B-Cell
/
Signal Transduction
Limits:
Humans
Language:
En
Year:
2012
Type:
Article