REGULATION OF THE APOPTOTIC RESPONSE TO RADIATION-DAMAGE IN B-CELL DEVELOPMENT

B lymphocyte precursor cells are ultrasensitive to DNA damage induced by irradiation and drugs and die by apoptosis at very low levels of ex posure. Previous studies have shown that this high level sensitivity i s p53-dependent, associated with very low level expression of Bcl-2 pr otein and can be reversed by expression of a bcl-2 transgene. We show here that transition from the pro-B to pre-B and then mature B cell st ages of murine lymphopoiesis is accompanied by changes in proliferatin g cells in sensitivity to X-irradiation induced apoptosis and that thi s is paralleled by variation in the ratio of anti-(Bcl-2/Bcl-(chi L)) to pro-(Bax) apoptotic proteins. These are however not fixed or invari ant features of developmental stage as they can be modulated by intera ctions via adhesive interactions with stromal cells, stromal proteins and growth factors. We interpret these data in the context of the stri ngent developmental regulation of clonal lymphopoiesis and the conting ency programming of cells that have extensive proliferative potential with a very low threshold for apoptosis following DNA damage.