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

Abstract

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.

The c-Myc-interacting adaptor protein Bin1 activates a caspase-independent cell death program

“…CD47 is a receptor for the antiangiogenic extracellular matrix protein thrombospondin. CD47 ligation engages a death program on chronic lymphocytic leukemia cells (Mateo et al, 1999). It is unclear whether these programs share any common aspect.…”

CD20-induced B cell death can bypass mitochondria and caspase activation

“…Although the clinical relevance is as yet uncertain, a role for caspase-independent apoptosis in the treatment of chemoresistant tumors was recently suggested. 20,23 Another cause of chemoresistance in hematologic malignancies may be the overexpression of Bcl-2, 48,62 which has been correlated with poor response to chemotherapy and poor prognosis in hematologic malignancies. [63][64][65][66] Hence, anti-neoplastic agents that act independent of Bcl-2 expression or the activation of caspases, may circumvent chemoresistance of their tumor targets.…”

“…9 Recently, several studies have described caspaseindependent forms of cell death, in which caspases are either not activated, or are activated but not essential for the induction of cell death. [20][21][22][23][24] Although in these latter studies cell death was not prevented by caspase inhibitors, nuclear features of apoptosis such as large-scale chromatin condensation and oligonucleosomal DNA fragmentation disappeared, indicating that active caspases are required for these characteristic nuclear features.…”

Staphylococcus aureus α-toxin-induced cell death: predominant necrosis despite apoptotic caspase activation

“…7 Although cell death mediated by both molecules was accompanied by caspase activation, the inhibition of these enzymes only blocked the apoptotic morphology, but not cell death itself. More recent examples include apoptosis induced during thymocyte development, 8 HIV-1 infection of primary T cells, 9 stimulation of surface antigens such as CD4, CD47 and CD99, [10][11][12] or CTLmediated target cell lysis. 13 In parallel, it became evident that apoptosis can also occur in the complete absence of caspase activation.…”