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.
Highlights
There is clear evidence that ionizing radiation (IR) causes leukemia
Applying multifactorial ANOVA to all data obtained in both populations, we found that apoptosis in umbilical cord blood (UCB) cells depended on dose and time after irradiation (p < 0.000001 and < 0.000001, respectively)
We found significant decrease in percentage of live CD34− lymphocytes from 3 to 24 h post-irradiation (p < 0.000001), while no statistically-significant decrease was revealed for CD34+ hematopoietic stem and progenitor cells (HSPC) (p = 0.09) suggesting lower radio-sensitivity of these cells
Summary
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. 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. Analysis of γH2AX fluorescence/early apoptotic pan-stained cells confirmed data from apoptosis showing lower level of endogenous DNA damage in HSC/MPP (CD34+CD38−) and progenitors (CD34+CD38+) compared to lymphocytes. We revealed induction of BCR-ABL PFG after low doses of IR, while high doses were not effective most probably due to apoptotic elimination of damaged PFG+ cells
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