Bcl-2 reduces mutant rates in a transgenic lacZ reporter gene in mouse pre-B lymphocytes.
To assess mutagenesis during early B-lymphocyte development in vitro, progenitor B cells (pre-B cells) were obtained from fetal livers of BALB/c mice and DBA/2N mice that harbored the transgenic shuttle vector, pUR288, with a lacZ reporter gene for the determination of mutant frequencies (MFs). Differentiation-arrested pre-B cells demonstrated a marked dose-dependent increase in lacZ mutant levels after exposure to gamma-irradiation with a peak MF of 250 x 10(-5) at 2.5 Gy. Without genotoxic treatment, pre-B cells undergoing spontaneous differentiation into surface IgM expressing immature B cells exhibited lacZ mutant levels of up to 95 x 10(-5). The mutational pattern was dominated in both experiments by illegitimate recombination mutations of lacZ, not point mutations. Likewise, in both experiments, the enforced expression of Bcl-2 resulted in a striking reduction of lacZ mutations. These findings indicated that mouse pre-B cells are prone to accumulate induced and self-inflicted mutations, particularly recombinations. Additionally, our studies revealed a heretofore unknown role of Bcl-2 in inhibiting mutagenesis during early B-cell development in mice.
Felix
Klaus
K
Laboratory of Genetics, Center for Cancer Research, National Cancer Institute, Room 2B10, Building 37, NIH, Bethesda, MD 20892-4255, USA.
Rolink
Antonius
A
Melchers
Fritz
F
Janz
Siegfried
S
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism* / Q000528:radiation effects; D002454:Cell Differentiation / Q000528:radiation effects; D005333:Fetus; D005720:Gamma Rays; D017930:Genes, Reporter; D005822:Genetic Vectors; D007763:Lac Operon; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016296:Mutagenesis / Q000528:radiation effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D011839:Radiation, Ionizing; D012190:Retroviridae / Q000235:genetics; D014162:Transfection
D019253:Proto-Oncogene Proteins c-bcl-2