Role of Mtd/Bok in normal and neoplastic B-cell development in the bursa of Fabricius

Abstract B-cell development in the bursa of Fabricius is accompanied by extensive apoptotic cell death. Apoptosis, however, is suppressed during c- myc -induced neoplasia. The experiments described here suggest that Mtd/Bok may drive apoptosis during normal development, and that this activity is blocked during myc -induced tumorigenesis. Bursal Mtd/Bok expression increases during development, correlating with the onset of intense, spontaneous apoptosis after hatching. Two isoforms of Mtd/Bok were characterized: WT-chMtd/Bok, found predominantly in the mitochondria and a less abundant form, lacking the presumptive transmembrane domain, Mtd/BokΔTM, found predominantly in the cytosol. Over-expression of Mtd/BokΔTM in a bursal lymphoma-derived cell line, DT40, reduced mitochondrial function and sensitized DT40 cells to apoptotic stimuli, while WT-chMtd/Bok had a diminished phenotype in these cells. In contrast, retroviral transduction of bursal stem cells with WT-chMtd/Bok ablated normal stem cell function in transplantation experiments, and produced extensive apoptosis in myc -induced pre-neoplastic bursal populations, but not in tumor cells.