Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling
Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling
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DOI：
10.1038/nature11309
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发表时间：
2012-09-13
期刊：
影响因子：
64.8
通讯作者：
Jumaa, Hassan
中科院分区：
文献类型：
--
作者：
Duehren-von Minden, Marcus;Uebelhart, Rudolf;Jumaa, Hassan
B细胞抗原受体（BCR）表达是慢性淋巴细胞白血病（CLL）的重要特征，CLL是西方国家最常见的B细胞肿瘤之一（1）。在不同的CLL患者中存在定型和准相同的BCR，表明特异性抗原的识别可能驱动CLL发病机制。在这里，我们表明，在其他B细胞肿瘤，CLL衍生的BCR诱导抗原非依赖性细胞自主信号，这是依赖于重链互补决定区（HCDR 3）和内部表位的BCR。事实上，转移CLL衍生的BCR的HCDR 3为非自主活性的BCR提供自主信号传导能力，而内部表位中的突变消除了这种能力。由于BCR表达是分泌型CLL衍生的BCR与靶细胞结合所必需的，并且内部表位的突变降低了这种结合，因此我们的研究结果表明了CLL发病机制的新模型，细胞自主抗原非依赖性信号传导是关键的致病机制。
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(1). 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.