Centre for Biological Signaling Studies (BIOSS), Albert-Ludwigs Universität Freiburg, 79104 Freiburg, Germany.
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.
B 细胞抗原受体 (BCR) 的表达是慢性淋巴细胞白血病 (CLL) 的一个重要特征，CLL 是西方国家最常见的 B 细胞肿瘤之一。不同 CLL 患者中存在定型和准同型 BCR 表明，识别特定抗原可能驱动 CLL 的发病机制。在这里，我们表明，与其他 B 细胞肿瘤不同，CLL 衍生的 BCR 诱导抗原非依赖性细胞自主信号，这依赖于重链互补决定区 (HCDR3) 和 BCR 的内部表位。事实上，将 CLL 衍生的 BCR 的 HCDR3 转移提供了自主信号能力，以非自主活跃的 BCR，而内部表位的突变则消除了这种能力。由于 BCR 的表达是分泌的 CLL 衍生的 BCR 与靶细胞结合所必需的，并且内部表位的突变减少了这种结合，我们的结果表明 CLL 发病机制的一个新模型，以细胞自主抗原非依赖性信号为关键发病机制。
