1. DNA damage response and preleukemic fusion genes induced by ionizing radiation in umbilical cord blood hematopoietic stem cells.
- Author
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Kosik P, Durdik M, Jakl L, Skorvaga M, Markova E, Vesela G, Vokalova L, Kolariková L, Horvathova E, Kozics K, and Belyaev I
- Subjects
- Antigens, CD34 metabolism, Apoptosis radiation effects, DNA Repair genetics, Fusion Proteins, bcr-abl genetics, Fusion Proteins, bcr-abl radiation effects, Gene Fusion genetics, Histones genetics, Histones metabolism, Humans, Infant, Newborn, Lymphocytes radiation effects, Preleukemia genetics, Radiation, Ionizing, Tumor Suppressor p53-Binding Protein 1 genetics, Tumor Suppressor p53-Binding Protein 1 metabolism, DNA Breaks, Double-Stranded radiation effects, Fetal Blood radiation effects, Gene Fusion radiation effects, Hematopoietic Stem Cells radiation effects, Leukemia genetics
- Abstract
There is clear evidence that ionizing radiation (IR) causes leukemia. For many types of leukemia, the preleukemic fusion genes (PFG), as consequences of DNA damage and chromosomal translocations, occur in hematopoietic stem and progenitor cells (HSPC) in utero and could be detected in umbilical cord blood (UCB) of newborns. However, relatively limited information is available about radiation-induced apoptosis, DNA damage and PFG formation in human HSPC. In this study we revealed that CD34+ HSPC compared to lymphocytes: (i) are extremely radio-resistant showing delayed time kinetics of apoptosis, (ii) accumulate lower level of endogenous DNA damage/early apoptotic γH2AX pan-stained cells, (iii) have higher level of radiation-induced 53BP1 and γH2AX/53BP1 co-localized DNA double stranded breaks, and (iv) after low dose of IR may form very low level of BCR-ABL PFG. Within CD34+ HSPC we identified CD34+CD38+ progenitor cells as a highly apoptosis-resistant population, while CD34+CD38- hematopoietic stem/multipotent progenitor cells (HSC/MPP) as a population very sensitive to radiation-induced apoptosis. Our study provides critical insights into how human HSPC respond to IR in the context of DNA damage, apoptosis and PFG.
- Published
- 2020
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