Implication of replicative stress-related stem cell ageing in radiation-induced murine leukaemia

Abstract

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. INTERPRETATION: 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.

Mouse Models for Efficacy Testing of Agents against Radiation Carcinogenesis — A Literature Review

“…Radiation, however, is not a likely candidate for the direct alteration of the second PU.1 allele in RI-AML cells, as IR does not induce point mutations observed in Sfpi 1 [81,88,94]. Point mutations are the most common type of spontaneous mutations and evidence suggest that Sfpi 1 mutations are of spontaneous origin [101,102]. …”

“…A mathematical model fitted to experimental data from cobblestone area forming cells (CAFC) and colony forming unit-granulocyte/macrophages (CFU-G/M) on ex vivo bone marrows revealed that irradiated HSCs cycle as much as ten times more quickly than those from unexposed animals [102]. Such increase in cycling is thought to also appear in vivo after irradiation.…”

Radiation-induced myeloid leukemia in murine models

“…In the case of the direct alteration of the Sfpi1 allele seen in RI-AML cells, however, radiation is not the most likely candidate, as IR does not induce the point mutations observed in Sfpi1 [ 85 , 93 , 99 ]. Evidence suggests that these mutations are of spontaneous origin, as point mutations are the most common of this type [ 108 , 109 ].…”

Mouse Models of Radiation-Induced Cancers

“…Experimental data suggest that radiation is primarily responsible for chromosome 2 deletions (Hayata et al, 1983;Peng et al, 2009;Trakhtenbrot et al, 1988), but point mutations in the DNAbinding domain of the second PU.1 Sfpi1 copy are likely due to delayed genomic instability (Boulton, Cleary, Papworth, & Plumb, 2001;Morgan, 2003;Plumb, Cleary, & Wright, 1998). These researches have fitted a mathematical model to ex vivo-expanded bone marrows of irradiated mice that revealed an accelerated cell cycle of HCS as compared to unirradiated controls (Ban & Kai, 2009). These mutations might originate through replicative stress following irradiation.…”