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Apoptosis

Mitochondria control of cell death induced by anti-HLA-DR antibodies

Leukemia volume 17, pages 1357–1365 (2003)Cite this article

Abstract

We have previously reported that crosslinking HLA-DR directly induces programmed cell death of malignant B cells. The present study further characterizes the biochemical mechanism for HLA-DR-mediated programmed cell death of tumor cells. Phosphatidylserine exposure on the plasma membrane and propidium iodide incorporation occur with very rapid kinetics and are observed as early as 10 min after the induction of cell death with anti-HLA-DR. In striking contrast to anti-CD95, we observe no activation of caspase-3, -8, or -9 upon anti-HLA-DR addition. Furthermore, the irreversible caspase inhibitor Z-VAD.fmk also failed to inhibit anti-HLA-DR-mediated cell death, further supporting the conclusion that HLA-DR induces cell death via a caspase-independent mechanism. We demonstrate that anti-HLA-DR-induced cell death is instead associated with a rapid disruption of the inner mitochondrial transmembrane potential, ΔΨm, a process that is significantly inhibited by Bcl-2 overexpression. Furthermore, we find that ΔΨm disruption results in the selective release of apoptosis-inducing factor (AIF) from the mitochondria. We propose that AIF is acting to initiate the morphological and biochemical changes observed in HLA-DR-mediated cell death.

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Authors and Affiliations

  1. Department of Oncology, Protein Design Labs, Inc., Fremont, CA, USA

    S K Bains, J Yun Tso & J M Green

  2. Division of Hematology-Oncology, The Ohio State University, Columbus, OH, USA

    A Mone, D Lucas & J C Byrd

  3. Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA

    G J Weiner

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  1. S K Bains
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  2. A Mone
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  3. J Yun Tso
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  4. D Lucas
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  6. G J Weiner
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  7. J M Green
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Correspondence to J M Green.

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Bains, S., Mone, A., Yun Tso, J. et al. Mitochondria control of cell death induced by anti-HLA-DR antibodies. Leukemia 17, 1357–1365 (2003). https://doi.org/10.1038/sj.leu.2402976

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