Induction of stem cell cycling in mice increases their sensitivity to a chemical leukaemogen: implications for inherited genomic instability and the bystander effect.

Abstract

Preconception paternal irradiation (PPI) modifies haemopoietic and stromal tissues of offspring and increases risk of generating lympho-haemopopietic malignancy if those offspring are then exposed to a leukaemogen. We hypothesised that this increased risk was related to inherited damage which had caused increased stem cell proliferation rates. To test for this link, in vivo, rapid stem cell proliferation was established by giving sub-lethal irradiation (3Gy gamma-rays) and allowing 3 days recovery. At this stage, 60% of haemopoietic spleen colony-forming units (CFU-S) were in DNA-synthesis, compared to <10% in unirradiated controls. Two groups of mice, unirradiated controls and irradiated animals, were then injected with 50mg/kg methyl nitrosourea (MNU) and observed daily for onset of lympho-haemopoietic malignancy. In a further control group of 60 mice, irradiated but not injected with MNU, only one leukaemia developed. In unirradiated controls, 20% of the mice developed malignancies between 3 and 8 months later: in the irradiated, MNU-treated groups, 95% developed malignancies between 2 and 7 months later. Thus, at least one powerful potentiating mechanism for induction of lympho-haemopoietc malignancy following inherited damage can be related to haemopoietic stem cell proliferation. Genomic instability is exposed by cell proliferation and has been implicated in this type of damage. However, a regulatory stromal microenvironment plays a part in inducing that proliferation. Thus, the microenvironment is the effective "bystander" which is thought to promote and amplify genomic instability, and thereby influence the induction of malignancy both in PPI offspring and in mice with induced stem cell proliferation.