RESUMEN

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.

Asunto(s)

Roturas del ADN de Doble Cadena/efectos de la radiación , Sangre Fetal/efectos de la radiación , Fusión Génica/efectos de la radiación , Células Madre Hematopoyéticas/efectos de la radiación , Leucemia/genética , Antígenos CD34/metabolismo , Apoptosis/efectos de la radiación , Reparación del ADN/genética , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/efectos de la radiación , Fusión Génica/genética , Histonas/genética , Histonas/metabolismo , Humanos , Recién Nacido , Linfocitos/efectos de la radiación , Preleucemia/genética , Radiación Ionizante , Proteína 1 de Unión al Supresor Tumoral P53/genética , Proteína 1 de Unión al Supresor Tumoral P53/metabolismo