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CD20-induced B cell death can bypass mitochondria and caspase activation

Leukemia volume 16, pages 1735–1744 (2002)Cite this article

Abstract

The apoptotic pathway activated by chimeric anti-CD20 monoclonal antibodies (rituximab, IDEC.C2B8) was analyzed using the Burkitt lymphoma cell line Ramos. Crosslinking of CD20 (CD20XL) induced apoptosis in Ramos cells, which involved loss of mitochondrial membrane potential (Δψm), the release of cytochrome-c (cyt-c), and activation of caspases-9 and -3. Nevertheless, several lines of evidence showed that the apoptotic outcome did not depend on these events. First, under circumstances where Ramos cells display resistance to either CD95- or B cell receptor (BCR)-induced apoptosis, CD20XL-induced apoptosis was not affected, pointing to a distinct pathway. Second, the broad-spectrum caspase inhibitor zVAD-fmk prevented processing of caspase-9, -3 and PARP as well as DNA fragmentation, but did not block apoptosis as measured by annexin V staining, cell size and membrane integrity. Lastly, Bcl-2 overexpression blocked cyt-c release and the decrease in Δψm, and completely prevented CD95- or BCR-mediated apoptosis; however, it did not affect CD20XL-induced cell death. We conclude that although CD20XL can initiate the mitochondrial apoptosis pathway, CD20-induced apoptosis does not necessarily require active caspases and cannot be blocked by Bcl-2. Since most chemotherapeutic drugs require the activation of caspases to exert their cytotoxicity, these findings provide an important rationale for the use of CD20 mAbs in chemoresistant malignancies.

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Acknowledgements

This work was sponsored in part by a grant from the Dutch Cancer Society to EE. We thank Peter Teeling of the Pathology Dept for his kind help with electronmicroscopy.

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  1. SMA Lens

    Present address: Dept of Molecular Biology, Netherlands Cancer Institute, Amsterdam, The Netherlands

Authors and Affiliations

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

    LE van der Kolk, LM Evers & MHJ van Oers

  2. Laboratory of Molecular Immunology, Columbia University, NY, USA

    C Omene & S Lederman

  3. Clinical Immunology Laboratory, Academic Medical Center, Amsterdam, The Netherlands

    RAW van Lier & E Eldering

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van der Kolk, L., Evers, L., Omene, C. et al. CD20-induced B cell death can bypass mitochondria and caspase activation. Leukemia 16, 1735–1744 (2002). https://doi.org/10.1038/sj.leu.2402559

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