CD47 ligation induces caspase-independent cell death in chronic lymphocytic leukemia.
Thrombospondin forms a 'molecular bridge' between phagocytic and apoptotic cells through interaction with alphavbeta3/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.
Mateo
V
V
Laboratoire d'allergie, Centre de Recherche du Centre Hospitalier de l' Université de Montréal, Hôpital Notre-Dame, 1560 rue Sherbrooke Est, Université de Montréal H2L 4M1, Quebec, Canada.
Lagneaux
L
L
Bron
D
D
Biron
G
G
Armant
M
M
Delespesse
G
G
Sarfati
M
M
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D051928:CD47 Antigen; D002352:Carrier Proteins / Q000276:immunology*; D020169:Caspases / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D008875:Middle Aged
D015703:Antigens, CD; D051928:CD47 Antigen; C497894:CD47 protein, human; D002352:Carrier Proteins; D020169:Caspases