1. Hematopoietic Stem Cells from Ts65Dn Mice Are Deficient in the Repair of DNA Double-Strand Breaks
- Author
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Daohong Zhou, Yingying Wang, Wei Feng, Jianhui Chang, Marie Chow, Yi Luo, Lijian Shao, Aimin Meng, and Wei Du
- Subjects
0301 basic medicine ,DNA Repair ,DNA repair ,Biophysics ,Biology ,Article ,Cell Line ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,DNA Breaks, Double-Stranded ,Radiology, Nuclear Medicine and imaging ,Radiation ,Hematopoietic stem cell ,Hematopoietic Stem Cells ,medicine.disease ,Haematopoiesis ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,Bone marrow ,Down Syndrome ,Stem cell ,Trisomy ,Chromosome 21 - Abstract
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.
- Published
- 2016