Down syndrome (DS) is a genetic disorder caused by the presence of an extra partial or whole copy of chromosome 21. In addition to musculoskeletal and neurodevelopmental abnormalities, children with DS exhibit various hematologic disorders and have an increased risk of developing acute lymphoblastic leukemia and acute megakaryocytic leukemia. Using the Ts65Dn mouse model, we investigated bone marrow defects caused by trisomy for 132 orthologs of the genes on human chromosome 21. The results showed that, although the total bone marrow cellularity as well as the frequency of hematopoietic progenitor cells (HPCs) was comparable between Ts65Dn mice and their age-matched euploid wild-type (WT) control littermates, human chromosome 21 trisomy led to a significant reduction in hematopoietic stem cell (HSC) numbers and clonogenic function in Ts65Dn mice. We also found that spontaneous DNA double-strand breaks (DSBs) were significantly increased in HSCs from the Ts65Dn mice, which was correlated with the significant reduction in HSC clonogenic activity compared to those from WT controls. Moreover, analysis of the repair kinetics of radiation-induced DSBs revealed that HSCs from Ts65Dn mice were less proficient in DSB repair than the cells from WT controls. This deficiency was associated with a higher sensitivity of Ts65Dn HSCs to radiation-induced suppression of HSC clonogenic activity than that of euploid HSCs. These findings suggest that an additional copy of genes on human chromosome 21 may selectively impair the ability of HSCs to repair DSBs, which may contribute to DS-associated hematological abnormalities and malignancies.
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1 June 2016
REGULAR ARTICLES|
May 31 2016
Hematopoietic Stem Cells from Ts65Dn Mice Are Deficient in the Repair of DNA Double-Strand Breaks
Yingying Wang;
Yingying Wang
aTianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical Collage, Tianjin 300192, China; and
bDivision of Radiation Health, Department of Pharmaceutical Sciences and
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Jianhui Chang;
Jianhui Chang
bDivision of Radiation Health, Department of Pharmaceutical Sciences and
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Lijian Shao;
Lijian Shao
bDivision of Radiation Health, Department of Pharmaceutical Sciences and
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Wei Feng;
Wei Feng
bDivision of Radiation Health, Department of Pharmaceutical Sciences and
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Yi Luo;
Yi Luo
bDivision of Radiation Health, Department of Pharmaceutical Sciences and
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Marie Chow;
Marie Chow
cDepartment of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205
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Wei Du;
Wei Du
bDivision of Radiation Health, Department of Pharmaceutical Sciences and
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Aimin Meng;
Aimin Meng
aTianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical Collage, Tianjin 300192, China; and
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Daohong Zhou
Daohong Zhou
1
bDivision of Radiation Health, Department of Pharmaceutical Sciences and
1Address for correspondence: University of Arkansas for Medical Sciences, Department of Pharmaceutical Sciences, 4301 W. Markham, no. 607, Little Rock, AR 72205; email: [email protected].
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Radiat Res (2016) 185 (6): 630–637.
Article history
Received:
February 05 2016
Accepted:
March 17 2016
Citation
Yingying Wang, Jianhui Chang, Lijian Shao, Wei Feng, Yi Luo, Marie Chow, Wei Du, Aimin Meng, Daohong Zhou; Hematopoietic Stem Cells from Ts65Dn Mice Are Deficient in the Repair of DNA Double-Strand Breaks. Radiat Res 1 June 2016; 185 (6): 630–637. doi: https://doi.org/10.1667/RR14407.1
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