Monoclonal antibodies directed to CD20 and HLA-DR can elicit homotypic adhesion followed by lysosome-mediated cell death in human lymphoma and leukemia cells.
Authors
Ivanov, AndreiBeers, 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
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 recordAbstract
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 InvestigationDOI
10.1172/JCI37884PubMed ID
19620786Type
ArticleLanguage
enISSN
1558-8238ae974a485f413a2113503eed53cd6c53
10.1172/JCI37884
Scopus Count
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