P53-Deficiency directly revealed the non-threshold leukemogenesis by a single administration of relatively low-dose of methyl nitrosourea

Quantitative increase in chemically induced leukemogenic sensitivity was seen in p53 deficient bone marrow (BM) cells, which was utilized to resolve the non-threshold issue directly. Methods: Because of induction of thymic lymphoma at a high frequency in the p53 K.O. mice, the transplantation assay (Hirabayashi, et al., 1997) was employed to focus on the hemopoietic system solely as a target tissue. Recipient mice were lethally irradiated and repopulated with either p53 deficient or wild BM cells. A graded doses of MNU by which incidence of hemopoietic neoplasms is less than 10% in the wild type were treated, i.p., to the recipients one month later when repopulation was completed. Results: All the mice repopulated by p53-deficient (p53−/−) BM and treated with over 14.8 mg/kg.bw died from hemopoietic malignancies by 100 days after the treatment, which was higher and faster than groups repopulated with p53+/− or wild type BM. In the group of p53−/−, including the 6.6 mg/kg-bw group, the days at the 50% incidence in hemopoietic neoplasms plotted showed a linear regression line, although those in the other groups, p53+/− and P53+/+, vanished on the middle of their own regression lines. The result clearly suggests, on one hand, that the extrapolation lines indicated were the non-threshold probabilistic appearance of neoplasms not only in heterozygous but also in the wild animals. However, because of DNA-repair and other molecular protection mechanism available in an intact animal, present study still can not answer the question whether a threshold might show up into a range of observation when experimental animals as a denominator could be increased infinitely in the wild type experimental animals.