Chronic Lymphocytic Leukaemia is Driven by Antigen-independent Cell-autonomous Signalling

Overview

Journal Nature

Specialty Science

Date 2012 Aug 14

PMID 22885698

Citations 250

Authors

Marcus Duhren-von Minden

Rudolf Ubelhart

Dunja Schneider

Thomas Wossning

Martina P Bach

Maike Buchner

Daniel Hofmann

Elena Surova

Marie Follo

Fabian Kohler

Hedda Wardemann

Katja Zirlik

Hendrik Veelken

Hassan Jumaa

Affiliations

Soon will be listed here.

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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