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CD47 ligation induces caspase-independent cell death in chronic lymphocytic leukemia

Nature Medicine volume 5, pages 1277–1284 (1999)Cite this article

Abstract

Thrombospondin forms a 'molecular bridge' between phagocytic and apoptotic cells through interaction with αvβ3/CD36. We report here that engagement of CD47, a newly described thrombospondin receptor, by immobilized monoclonal antibody against CD47 or by thrombospondin induced in all B-cell chronic lymphocytic leukemia clones the cytoplasmic features of apoptosis (cell shrinkage, decrease in mitochondrial transmembrane potential and phosphatidylserine externalization) without the nuclear features (chromatin condensation, appearance of single-stranded DNA, DNA fragmentation and cleavage of poly ADP-ribose polymerase). These cytoplasmic events of apoptosis were not prevented by the addition of caspase inhibitor z-VAD-fmk, or by the presence of survival factors (such as interleukin-4 and gamma interferon) or cell activation. Morphological studies confirmed the integrity of the nucleus and showed swelling of the mitochondria. This caspase-independent death pathway may be relevant to the development of alternate therapeutic strategies in chronic lymphocytic leukemia, which remains an incurable disease.

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Figure 1: CD5 and CD23 expression on B-CLL lymphocytes after treatment with monoclonal antibody against CD47.
Figure 2: CD47 ligation by immobilized monoclonal antibody against CD47 or by thrombospondin (TSP) induces apoptosis in B-CLL cells.
Figure 3: Induction of apoptosis by monoclonal antibody against CD47 is CD47-mediated but not Fc-mediated and requires CD47 cross-linking.
Figure 4: Apoptosis induced by monoclonal antibody against CD47 is not prevented by survival factors or cell activation.
Figure 5: CD47 ligation induces a caspase-independent cell death.
Figure 6: Morphology of B-CLL cells treated with monoclonal antibody against CD47.
Figure 7: Electron micrographs of B-CLL cells.

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Acknowledgements

We thank the Department of Pathology (Notre-Dame Hospital) for the electron microscopy data. This work was supported by MRC grant numbers MT 13311 and MT 14432 and Fondation Medic "Fulpius".

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Authors and Affiliations

  1. Laboratoire d'allergie, Centre de Recherche du Centre Hospitalier de l' Université de Montréal, ôpital Notre-Dame, Université de Montréal, 1560 rue Sherbrooke Est, H2L 4M1, Quebec, Canada

    V. Mateo, G. Delespesse & M. Sarfati

  2. Département d'hématologie, Institut Bordet, Bruxelles, Belgique

    L. Lagneaux & D. Bron

  3. Département d'hématologie, Centre Hospitalier de l' Université de Montréal, Hôpital Notre-Dame, Université de Montréal, Canada

    G. Biron

  4. Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

    M. Armant

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Correspondence to M. Sarfati.

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Mateo, V., Lagneaux, L., Bron, D. et al. CD47 ligation induces caspase-independent cell death in chronic lymphocytic leukemia. Nat Med 5, 1277–1284 (1999). https://doi.org/10.1038/15233

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