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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 ori...

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Autores principales: Ban, N, Kai, M
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720201/
https://www.ncbi.nlm.nih.gov/pubmed/19513063
http://dx.doi.org/10.1038/sj.bjc.6605135
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author Ban, N
Kai, M
author_facet Ban, N
Kai, M
author_sort Ban, N
collection PubMed
description 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.
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spelling pubmed-27202012010-07-21 Implication of replicative stress-related stem cell ageing in radiation-induced murine leukaemia Ban, N Kai, M Br J Cancer Genetics and Genomics 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. Nature Publishing Group 2009-07-21 2009-06-09 /pmc/articles/PMC2720201/ /pubmed/19513063 http://dx.doi.org/10.1038/sj.bjc.6605135 Text en Copyright © 2009 Cancer Research UK https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.
spellingShingle Genetics and Genomics
Ban, N
Kai, M
Implication of replicative stress-related stem cell ageing in radiation-induced murine leukaemia
title Implication of replicative stress-related stem cell ageing in radiation-induced murine leukaemia
title_full Implication of replicative stress-related stem cell ageing in radiation-induced murine leukaemia
title_fullStr Implication of replicative stress-related stem cell ageing in radiation-induced murine leukaemia
title_full_unstemmed Implication of replicative stress-related stem cell ageing in radiation-induced murine leukaemia
title_short Implication of replicative stress-related stem cell ageing in radiation-induced murine leukaemia
title_sort implication of replicative stress-related stem cell ageing in radiation-induced murine leukaemia
topic Genetics and Genomics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2720201/
https://www.ncbi.nlm.nih.gov/pubmed/19513063
http://dx.doi.org/10.1038/sj.bjc.6605135
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