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

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 countries1. 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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Figure 1: CLL-derived BCRs possess autonomous signalling capacity.
Figure 2: CLL BCRs induce cell-autonomous signalling.
Figure 3: Autonomous signalling of CLL-derived BCRs is mediated by the recognition of a BCR-intrinsic epitope.
Figure 4: Cell-autonomous Ca 2+ signalling is elevated in primary CLL B cells.

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Acknowledgements

We thank C. Croce for providing the TCL1 mice, M. Reth and P. Nielsen for scientific discussion and reading the manuscript, C. Wehr for help cloning TCL1-derived BCRs, A. Ott, A. Würch, S. Hopitz and B. Wehrle for help with FACS experiments and cloning, and D. Pfeifer and M. Pantic for providing clinical data. This work was supported by the Deutsche Krebshilfe (Project 108935), the Deutsche Forschungsgemeinschaft (SFB746 and JU 463/2-1) and the Excellence Initiative of the German Federal and State Governments (GSC-4, Spemann Graduate School).

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M.D.-v.M., R.Ü., D.S., F.K. and M.P.B. conducted cloning of BCRs. M.D.-v.M., R.Ü. and D.S. performed measurements of BCR surface expression and calcium flux and performed soluble BCR-binding assays. M.D.-v.M. and T.W. performed quantitative reverse-transcriptase PCR experiments. M.B. performed the NF-κB activity ELISA. E.S. analysed Vh region sequences from patient samples. M.D.-v.M. and M.F. performed single-cell Ca2+ measurements. D.H. and H.W. tested the polyreactivity of CLL and TCL1 receptors. K.Z. and H.V. conducted the characterization of lymphoma patients and provided samples. M.D.-v.M., T.W., F.K. and H.J. wrote the manuscript. H.J. designed experiments. All authors discussed the results and commented on the manuscript.

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Correspondence to Hassan Jumaa.

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The authors declare no competing financial interests.

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Minden, M., Übelhart, R., Schneider, D. et al. Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling. Nature 489, 309–312 (2012). https://doi.org/10.1038/nature11309

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