Implication of replicative stress-related stem cell ageing in radiation-induced murine leukaemia.
BACKGROUND
The essential aetiology of radiation-induced acute myeloid leukaemia (AML) in mice is the downregulation of the transcription factor PU.1. The causative mutation of the PU.1-endocing Sfpi1 gene consists mostly of C:G to T:A transitions at a CpG site and is likely to be of spontaneous origin. To work out a mechanism underlying the association between radiation exposure and the AML induction, we have hypothesised that replicative stress after irradiation accelerates the ageing of haematopoietic stem cells (HSCs), and the ageing-related decline in DNA repair could affect the spontaneous mutation rates.


METHODS
Mathematical model analysis was conducted to examine whether and to what extent the cell kinetics of HSCs can be modified after irradiation. The haematopoietic differentiation process is expressed as a mathematical model and the cell-kinetics parameters were estimated by fitting the simulation result to the assay data.


RESULTS
The analysis revealed that HSCs cycle vigourously for more than a few months after irradiation. The estimated number of cell divisions per surviving HSC in 3 Gy-exposed mice reached as high as ten times that of the unexposed.


CONCLUSIONS
The mitotic load after 3 Gy irradiation seems to be heavy enough to accelerate the ageing of HSCs and the hypothesis reasonably explains the leukaemogenic process.
Ban
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Department of Health Sciences, Oita University of Nursing and Health Sciences, 2944-9 Megusuno, Oita 870-1201, Japan. ban@oita-nhs.ac.jp
Kai
M
M
D000208:Acute Disease; D000818:Animals; D002455:Cell Division / Q000502:physiology / Q000528:radiation effects*; D016922:Cellular Senescence / Q000502:physiology / Q000528:radiation effects*; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D007951:Leukemia, Myeloid / Q000209:etiology / Q000473:pathology*; D007953:Leukemia, Radiation-Induced / Q000473:pathology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008938:Mitosis / Q000502:physiology / Q000528:radiation effects; D008954:Models, Biological