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Implication of replicative stress-related stem cell ageing in radiation-induced murine leukaemia.
- Source :
-
British Journal of Cancer . 7/21/2009, Vol. 101 Issue 2, p363-371. 9p. 3 Diagrams, 1 Chart, 5 Graphs. - Publication Year :
- 2009
-
Abstract
- <bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Interpretation: </bold>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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00070920
- Volume :
- 101
- Issue :
- 2
- Database :
- Academic Search Index
- Journal :
- British Journal of Cancer
- Publication Type :
- Academic Journal
- Accession number :
- 43200741
- Full Text :
- https://doi.org/10.1038/sj.bjc.6605135