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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Morton, L. M. et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992–2001. Blood 107, 265–276 (2006)
Ghiotto, F. et al. Remarkably similar antigen receptors among a subset of patients with chronic lymphocytic leukemia. J. Clin. Invest. 113, 1008–1016 (2004)
Stamatopoulos, K. et al. Over 20% of patients with chronic lymphocytic leukemia carry stereotyped receptors: pathogenetic implications and clinical correlations. Blood 109, 259–270 (2007)
Bikos, V. et al. Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications. Leukemia 26, 1638–1646 (2012)
Widhopf, G. F., II et al. Chronic lymphocytic leukemia B cells of more than 1% of patients express virtually identical immunoglobulins. Blood 104, 2499–2504 (2004)
Ghia, P., Chiorazzi, N. & Stamatopoulos, K. Microenvironmental influences in chronic lymphocytic leukaemia: the role of antigen stimulation. J. Intern. Med. 264, 549–562 (2008)
Stevenson, F. K., Krysov, S., Davies, A. J., Steele, A. J. & Packham, G. B-cell receptor signaling in chronic lymphocytic leukemia. Blood 118, 4313–4320 (2011)
Köhler, F. et al. Autoreactive B cell receptors mimic autonomous pre-B cell receptor signaling and induce proliferation of early B cells. Immunity 29, 912–921 (2008)
Übelhart, R. et al. N-linked glycosylation selectively regulates autonomous precursor BCR function. Nature Immunol. 11, 759–765 (2010)
Hervé, M. et al. Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity. J. Clin. Invest. 115, 1636–1643 (2005)
Sthoeger, Z. M. et al. Production of autoantibodies by CD5-expressing B lymphocytes from patients with chronic lymphocytic leukemia. J. Exp. Med. 169, 255–268 (1989)
Meixlsperger, S. et al. Conventional light chains inhibit the autonomous signaling capacity of the B cell receptor. Immunity 26, 323–333 (2007)
Bichi, R. et al. Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression. Proc. Natl Acad. Sci. USA 99, 6955–6960 (2002)
Herling, M. et al. High TCL1 levels are a marker of B-cell receptor pathway responsiveness and adverse outcome in chronic lymphocytic leukemia. Blood 114, 4675–4686 (2009)
Yan, X. J. et al. B cell receptors in TCL1 transgenic mice resemble those of aggressive, treatment-resistant human chronic lymphocytic leukemia. Proc. Natl Acad. Sci. USA 103, 11713–11718 (2006)
Binder, M. et al. B-cell receptor epitope recognition correlates with the clinical course of chronic lymphocytic leukemia. Cancer 117, 1891–1900 (2011)
Kulathu, Y., Grothe, G. & Reth, M. Autoinhibition and adapter function of Syk. Immunol. Rev. 232, 286–299 (2009)
Herishanu, Y. et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-κB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood 117, 563–574 (2011)
Seiler, T. et al. Characterization of structurally defined epitopes recognized by monoclonal antibodies produced by chronic lymphocytic leukemia B cells. Blood 114, 3615–3624 (2009)
Buchner, M. et al. Spleen tyrosine kinase inhibition prevents chemokine- and integrin-mediated stromal protective effects in chronic lymphocytic leukemia. Blood 115, 4497–4506 (2010)
Suljagic, M. et al. The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the Eμ–TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor signaling. Blood 116, 4894–4905 (2010)
Friedberg, J. W. et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 115, 2578–2585 (2010)
Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors . Science 301, 1374–1377 (2003)
Tiller, T. et al. Development of self-reactive germinal center B cells and plasma cells in autoimmune FcγRIIB-deficient mice . J. Exp. Med. 207, 2767–2778 (2010)
Bertinetti, C. et al. Cloning of idiotype immunoglobulin genes in B cell lymphomas by anchored PCR and production of individual recombinant idiotype vaccines in Escherichia coli . Eur. J. Haematol. 77, 395–402 (2006)
Osterroth, F. et al. Rapid expression cloning of human immunoglobulin Fab fragments for the analysis of antigen specificity of B cell lymphomas and anti-idiotype lymphoma vaccination. J. Immunol. Methods 229, 141–153 (1999)
Su, Y. W. & Jumaa, H. LAT links the Pre-BCR to calcium signaling. Immunity 19, 295–305 (2003)
Storch, B., Meixlsperger, S. & Jumaa, H. The Ig-α ITAM is required for efficient differentiation but not proliferation of pre-B cells. Eur. J. Immunol. 37, 252–260 (2007)
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).
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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