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Chronic lymphocytic leukemia

Targeting antigen-independent proliferation in chronic lymphocytic leukemia through differential kinase inhibition

Leukemia volume 31, pages 2601–2607 (2017)Cite this article

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Abstract

The clinical success of B-cell receptor (BCR) signaling pathway inhibitors in chronic lymphocytic leukemia (CLL) is attributed to inhibition of adhesion in and migration towards the lymph node. Proliferation of CLL cells is restricted to this protective niche, but the underlying mechanism(s) is/are not known. Treatment with BCR pathway inhibitors results in rapid reductions of total clone size, while CLL cell survival is not affected, which points towards inhibition of proliferation. In vitro, BCR stimulation does not induce proliferation of CLL, but triggering via Toll-like receptor, tumor necrosis factor or cytokine receptors does. Here, we investigated the effects of clinically applied inhibitors that target BCR signaling, in the context of proliferation triggered either via CD40L/IL-21 or after CpG stimulation. CD40L/IL-21-induced proliferation could be inhibited by idelalisib and ibrutinib. We demonstrate this was due to blockade of CD40L-induced ERK-signaling. Targeting JAKs, but not SYK, blocked CD40L/IL-21-induced proliferation. In contrast, PI3K, BTK as well as SYK inhibition prevented CpG-induced proliferation. Knockdown experiments showed that CD40L/IL-21 did not co-opt upstream BCR components such as CD79A, in contrast to CpG-induced proliferation. Our data indicate that currently applied BTK/PI3K inhibitors target antigen-independent proliferation in CLL, and suggest that targeting of JAK and/or SYK might be clinically useful.

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Acknowledgements

We thank the CLL patients for their blood donations and collaboration in this study. This work was supported by a grant from the Dutch Cancer Foundation (number UVA 2011-5097) to APK.

Author contributions

ES and RT designed, performed and interpreted experiments. ES analyzed the results and prepared the figures. ES, EE and APK wrote the paper. RT contributed to writing. EE and APK supervised this study.

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Author notes

  1. A P Kater and E Eldering: Shared senior authorship.

Authors and Affiliations

  1. Department of Experimental Immunology, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands

    E Slinger, R Thijssen & E Eldering

  2. Department of Hematology, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands

    E Slinger, R Thijssen & A P Kater

  3. Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands

    A P Kater & E Eldering

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  1. E Slinger
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Correspondence to E Eldering.

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Slinger, E., Thijssen, R., Kater, A. et al. Targeting antigen-independent proliferation in chronic lymphocytic leukemia through differential kinase inhibition. Leukemia 31, 2601–2607 (2017). https://doi.org/10.1038/leu.2017.129

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