| Cell death has become one of the most studied biologic research fields for the last ten years. Novel insights have enriched seminal discoveries in cell-death processes. The work presented in this thesis contributed to this knowledge.;We herein report the description of a novel form of cell death, induced by ligation of the ubiquitously expressed CD47 antigen. The cell death was characterized by the cytoplasmic features of apoptosis including cell shrinkage, phosphatidylserine f (PS) exposure to the outer leaflet of the cytoplasmic membrane and drop in mitochondrial membrane potential with maintenance of cytoplasmic membrane integrity. By contrast, caspases, the proteolytic enzymes responsible for the major biochemical and morphological changes observed during apoptosis, remained in their unprocessed forms and inactivated. In addition, no nuclear changes were observed during this novel cell-death process. CD47-induced cell-death signaling required the extracellular and transmembrane domains of the molecule. No other known CD47 signaling pathways appeared to be involved during this cell death process. However, cytoskeleton reorganization, cell volume regulation by potassium efflux, and an antimycin A sensitive signaling pathway were implicated in CD47-induced cell-death signal.;This novel cell-death can be triggered in various cell lines of the hematopoietic system and in B-cells from chronic lymphocytic leukemia patients (B-CLL). Nonetheless, hematopoietic stem cells, the renewal source of the lymphocytic and myeloid pools remained totally resistant to CD47-induced killing. We observed CD47-induced cell-death in all B-CLL patients tested regardless the presence of survival factors that are thought to be responsible for the incurable state of the disease. Moreover, B-CLL killed by CD47 ligation were efficiently cleared by immature dendritic cells through a phagocytosis mechanism, indicating that this previously non-described cell-death process was effective. The discovery and characterization of CD47-induced caspase-independent cell-death might open new therapeutic avenues for B-CLL disease. |
