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

Nature. 2012 Sep 13;489(7415):309-12. doi: 10.1038/nature11309.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Autoantigens / immunology
  • Autoantigens / metabolism
  • Calcium Signaling
  • Complementarity Determining Regions / immunology
  • Complementarity Determining Regions / metabolism
  • Epitopes, B-Lymphocyte / immunology
  • Epitopes, B-Lymphocyte / metabolism
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / immunology
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology*
  • Receptors, Antigen, B-Cell / immunology
  • Receptors, Antigen, B-Cell / metabolism*
  • Signal Transduction*


  • Autoantigens
  • Complementarity Determining Regions
  • Epitopes, B-Lymphocyte
  • Receptors, Antigen, B-Cell