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    Monoclonal antibodies directed to CD20 and HLA-DR can elicit homotypic adhesion followed by lysosome-mediated cell death in human lymphoma and leukemia cells.

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    Authors
    Ivanov, Andrei
    Beers, Stephen A
    Walshe, Claire A
    Honeychurch, Jamie
    Alduaij, Waleed
    Cox, Kerry L
    Potter, Kathleen N
    Murray, Stephen M
    Chan, Claude H T
    Klymenko, Tetyana
    Erenpreisa, Jekaterina
    Glennie, Martin J
    Illidge, Timothy M
    Cragg, Mark S
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    Affiliation
    CRUK Paterson Institute for Cancer Research, School of Cancer and Imaging Sciences, School of Medicine, University of Manchester, Manchester, United Kingdom.
    Issue Date
    2009-08
    
    Metadata
    Show full item record
    Abstract
    mAbs are becoming increasingly utilized in the treatment of lymphoid disorders. Although Fc-FcgammaR interactions are thought to account for much of their therapeutic effect, this does not explain why certain mAb specificities are more potent than others. An additional effector mechanism underlying the action of some mAbs is the direct induction of cell death. Previously, we demonstrated that certain CD20-specific mAbs (which we termed type II mAbs) evoke a nonapoptotic mode of cell death that appears to be linked with the induction of homotypic adhesion. Here, we reveal that peripheral relocalization of actin is critical for the adhesion and cell death induced by both the type II CD20-specific mAb tositumomab and an HLA-DR-specific mAb in both human lymphoma cell lines and primary chronic lymphocytic leukemia cells. The cell death elicited was rapid, nonapoptotic, nonautophagic, and dependent on the integrity of plasma membrane cholesterol and activation of the V-type ATPase. This cytoplasmic cell death involved lysosomes, which swelled and then dispersed their contents, including cathepsin B, into the cytoplasm and surrounding environment. The resulting loss of plasma membrane integrity occurred independently of caspases and was not controlled by Bcl-2. These experiments provide what we believe to be new insights into the mechanisms by which 2 clinically relevant mAbs elicit cell death and show that this homotypic adhesion-related cell death occurs through a lysosome-dependent pathway.
    Citation
    Monoclonal antibodies directed to CD20 and HLA-DR can elicit homotypic adhesion followed by lysosome-mediated cell death in human lymphoma and leukemia cells. 2009, 119 (8):2143-59 J. Clin. Invest.
    Journal
    The Journal of Clinical Investigation
    URI
    http://hdl.handle.net/10541/85227
    DOI
    10.1172/JCI37884
    PubMed ID
    19620786
    Type
    Article
    Language
    en
    ISSN
    1558-8238
    ae974a485f413a2113503eed53cd6c53
    10.1172/JCI37884
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research
    School of Cancer and Imaging Sciences

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