DNA-DAMAGE CAN INDUCE APOPTOSIS IN PROLIFERATING LYMPHOID-CELLS VIA P53-INDEPENDENT MECHANISMS INHIBITABLE BY BCL-2

The roles of p53 as an inducer and Bcl-2 as an inhibitor of apoptotic death were explored in lymphoid cells. Lymphocytes from p53(-/-) mice were radioresistant, but unexpectedly, cycling T lymphoma cells and mi togenically activated T lymphocytes from these animals underwent apopt osis after irradiation or genotoxic drug treatment. Hence, p53 is not the only mediator of apoptosis provoked by DNA damage. Irradiated p53( -/-) lymphoblasts expressing Bcl-2 were subject to growth arrest but r esisted apoptosis. Their accumulation in G1 as well as G2 is suggestiv e of a p53-independent DNA-damage G1 checkpoint. Since Bcl-2 increased the clonogenic survival of the irradiated cells, expression of surviv al genes may pose a greater impediment to genotoxic cancer therapy tha n loss of p53.