Abstract
The essential etiology of radiation-induced acute myeloid leukemia (AML) in mice is the downregulation of the transcription factor PU.1. It usually results from a deletion of the PU.1-coding chromosomal region and a mutation of the retained allele. Interestingly, the latter mutation 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 hypothesized that replicative stress after irradiation accelerates the aging of hematopoietic stem cells (HSCs), and the aging-related decline in DNA repair could affect the spontaneous mutation rates. Mathematical model analysis was conducted to examine whether and to what extent the cell-kinetics of HSCs can be modified after irradiation. The hematopoietic differentiation process is expressed as a linear compartment model and the cell-kinetics parameters were estimated by fitting the simulation result to the assay data. The analysis showed the upregulated cell kinetics for HSCs after 3 Gy-irradiation, which seemed to be sufficient to accelerate aging of them. Possible leukemogenic processes have been discussed based on the results, and we have found the most plausible explanation is that the replicative stress-related stem cell aging plays a role elevating spontaneous mutation rates of HSCs and their progeny.
