DNA damage response and preleukemic fusion genes induced by ionizing radiation in umbilical cord blood hematopoietic stem cells.

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.

La familia de tumores del sarcoma de Ewing / No disponible

La familia de tumores del sarcoma de Ewing (SE) es un conjunto de neoplasias primarias del hueso y/o tejidos de soporte, causado por la proliferación de células madre mesenquimales bloqueadas en su maduración fetal y que adquieren posteriormente las características de células malignas. Este conjunto de enfermedades se caracterizan por una firma molecular que las define: la fusión del gen EWS del cromosoma 22q12 con genes implicados en el control de la replicación celular, creando un gen de fusión anómalo. Los genes de fusión o sus productos se detectan mediante la PCR de RNA o RT-PCR. Virtualmente todos los enfermos con SE tienen enfermedad microscópica subclínica, por ello el tratamiento eficaz del SE es por vía sistémica. La probabilidad de supervivencia libre de enfermedad de los pacientes sin metástasis detectables clínicamente es del 70%; para los pacientes con metástasis es inferior al 30%. La quimioterapia es el tratamiento esencial para el control de la enfermedad microscópica sistémica, pero sola no puede erradicar la enfermedad en forma de grandes masas. El control local de la enfermedad visible debe realizarse mediante cirugía y/o radioterapia. El objetivo fundamental de la cirugía es obtener márgenes de resección amplios. El SE es un tumor radiosensible y dada la sinergia entre la quimioterapia y la radioterapia, los tratamientos suelen ser combinados(AU)

The Ewing family of tumors (SE) is a group of neoplasias arising from developing bone or soft tissues. SE is likely derived from the malignant proliferation of mesenchymal stem cells. This group of diseases has a unique molecular signature: the fusion of the EWS gene on chromosome 22q12 to genes involved in the control of cell proliferation, generating an abnormal fusion gene. The fusion genes and their products are detected in the laboratory by the RTPCR method. Virtually all SE patients have subclinical microscopic disease; therefore effective treatment must always include systemic chemotherapy. The event-free survival for patients without clinically detectable disease is 70% at 5 years from diagnosis; for patients with metastasis at diagnosis is less than 30%. Chemotherapy is essential for the treatment of microscopic metastatic disease, but it cannot eradicate the disease in the form of masses. The local control of the disease is made by surgery and/or radiation therapy. The main objective of surgery is to achieve tumor resection with ample margins. The SE is a radiosensitive tumor and because the synergistic effect with chemotherapy, they are used in combination. In summary: SE is a rare, complex and life-threatening group of diseases that should be managed in comprehensive cancer centers(AU)

Chronic myelogenous leukemia stem and progenitor cells demonstrate chromosomal instability related to repeated breakage-fusion-bridge cycles mediated by increased nonhomologous end joining.

Chromosomal aberrations are an important consequence of genotoxic exposure and contribute to pathogenesis and progression of several malignancies. We investigated the susceptibility to chromosomal aberrations in chronic myelogenous leukemia (CML) progenitors after exposure to ionizing radiation. In normal progenitors, ionizing radiation induced both stable and unstable chromosomal lesions, but only stable aberrations persisted after multiple divisions. In contrast, radiation of chronic phase CML progenitors resulted in enhanced generation of unstable lesions that persisted after multiple divisions. CML progenitors demonstrated active cell cycle checkpoints and increased nonhomologous end joining DNA repair, suggesting that persistence of unstable aberrations was the result of continued generation of these lesions. CML progenitors demonstrated enhanced susceptibility to repeated cycles of chromosome damage, repair, and damage through a breakage-fusion-bridge mechanism. Perpetuation of breakage-fusion-bridge cycles in CML progenitors was mediated by classic nonhomologous end joining repair. These studies reveal a previously unrecognized mechanism of chromosomal instability in leukemia progenitors because of continued generation of unstable chromosomal lesions through repeated cycles of breakage and repair of such lesions.

[Influence of irradiation on the dynamic three-dimension distribution of abl and bcr genes in the interphase nuclei of IM-9 cell].

OBJECTIVE: To investigate the material foundation of the fusion of bcr and abl genes, and to explore the pathogenesis of chronic myeloid leukemia. METHODS: By FISH combined with laser confocal scanning microscopy, the three-dimension (3D) distribution of bcr and abl genes in the interphase nuclei of normal and irradiated IM-9 cells was studied in each cell cycle phases. RESULTS: abl and bcr genes distributed non-randomly in the interphase nuclei of IM-9 cells. abl gene preferably located at the outer layer and bcr near the core of the nucleus. The two genes were drawn near each other most in G(0) phase. The relative distance between the homologous genes was greater at proliferation phase than at quiescence phase. After irradiation, the relative distances from the two genes to the core and between the two genes were shortened, with the shortest distance between the two genes in S phase. CONCLUSION: Irradiation could change the 3D-distribution of abl and bcr genes in the interphase nuclei of IM-9 cell and accelerate them to draw near each other.