The Non-Death Domain Containing TNFR Member HVEM Induces Apoptosis and Chemokine Production on B-Chronic Lymphocytic Leukemia Cells.

B-cell chronic lymphocytic leukemia (B-CLL) is the most common adult leukemia and it still remains incurable. New therapies are required for this disease characterized by failure of mature lymphocytes to undergo apoptosis. Members of tumor necrosis factor receptors (TNFR) family play important roles in cell activation, proliferation, differentiation and apoptosis. We focused our study on HVEM (Herpes virus entry mediator), devoid of intracytoplasmic death domain, which is known to costimulate T- and B-cell activation, and its ligand LIGHT. Surprisingly, we found that LIGHT, as well as some anti-HVEM antibodies, induced apoptosis of B-CLL cells. This apoptosis was associated with activation of caspase-3, -8 and -9, decrease in mitochondrial membrane potential, and upregulation of the pro-apoptotic protein Bax. Importantly, the efficiency of HVEM-cell killing compared favorably with that of the pan-B cell therapeutic monoclonal antibody Rituximab. In addition, HVEM induced upregulation of various cytokines and chemokines, and a major increase in IL-8 secretion. Thus, HVEM stimulation induces apoptosis of B-CLL cells and could potentially also participate in the recruitment of immune effectors, and may therefore be useful for clinical treatment of this malignancy.