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Dichotomy in NF-κB signaling and chemoresistance in immunoglobulin variable heavy-chain-mutated versus unmutated CLL cells upon CD40/TLR9 triggering

Oncogene volume 29, pages 5071–5082 (2010)Cite this article

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Abstract

Chronic lymphocytic leukemia (CLL) cells circulating in peripheral blood (PB) differ from the leukemic fraction in lymph nodes (LNs) with respect to cell division and drug sensitivity. CD40 stimulation of PB CLL cells in vitro results in chemoresistance and provides a partial model for the LN microenvironment. The TLR9 ligand CpG induces proliferation in immunoglobulin variable heavy-chain-unmutated CLL, but apoptosis in immunoglobulin variable heavy-chain-mutated CLL. To juxtapose proliferative with antiapoptotic signals, we investigated the effects of CpG in the context of CD40 ligation in mutated versus unmutated CLL cells in this study. Prolonged CD40 ligation induced classical, followed by alternative nuclear factor-κB (NF-κB), activity in both subgroups, correlating with enhanced Bfl-1 and Bcl-XL levels, respectively. A dichotomy in NF-κB signaling occurred on combined CD40/TLR9 triggering. This induced declining p52 and Bcl-XL levels, and reversed chemoresistance only in mutated cells, whereas unmutated cells proliferated, maintained p52 and Bcl-XL and remained chemoresistant. The pivotal contribution of Bcl-XL to chemoresistance was shown by the BH3 mimetic ABT-737 and RNA interference. Finally, in ex vivo LN samples, p52, p65 and Bcl-XL levels were highly expressed, corroborating the in vitro findings. Thus, a distinction in NF-κB activation and drug susceptibility in mutated versus unmutated (LN-like) CLL cells was uncovered, which was causally linked to Bcl-XL levels.

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Acknowledgements

We thank professor Carel JM van Noessel and Dr Richard Bende (department of pathology, AMC) for obtaining lymph node material of CLL patients. We are very grateful to the patients for donating blood samples. ABT-737, a BH3 mimetic, was obtained under MTA from Abbott (Abbott Park, courtesy Dr S Rosenberg). This work was supported by the Dutch Cancer Society (KWF), Grant no. UvA 2007-3856.

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Authors and Affiliations

  1. Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    J M Tromp, S H Tonino, J A Elias, D M Luijks, A P Kater & M H J van Oers

  2. Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    J M Tromp, S H Tonino, J A Elias, A Jaspers, R A W van Lier & E Eldering

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  1. J M Tromp
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  2. S H Tonino
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Tromp, J., Tonino, S., Elias, J. et al. Dichotomy in NF-κB signaling and chemoresistance in immunoglobulin variable heavy-chain-mutated versus unmutated CLL cells upon CD40/TLR9 triggering. Oncogene 29, 5071–5082 (2010). https://doi.org/10.1038/onc.2010.248

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