RESUMEN
Chronic myeloid leukemia (CML) is caused by a BCR-ABL chromosome translocation in a primitive hematopoietic stem cell. The number of hematopoietic stem cells in the body is thus a major factor in CML risk. Evidence suggests that the number of hematopoietic stem cells in the body is only loosely regulated, having a broad "dead-band" of physiologically acceptable values. The existence of a dead-band is important, because it would imply that low levels of hematopoietic stem cell killing can be permanent; i.e., it would imply that low doses of ionizing radiation can cause permanent reductions in the total number of CML target cells and thus permanent reductions in the subsequent risk of spontaneous CML. Such reductions in risk could be substantial if hematopoietic stem cells are also hypersensitive to radiation killing at low dose. Our calculations indicate that, due to dead-band hematopoietic stem cell control, if hematopoietic stem cells are as hypersensitive to killing at low doses as epithelial cells, reductions in the spontaneous CML risk could exceed the low-dose risks of induced CML; i.e., the net lifetime CML risk could have a U-shaped dose-response curve.
Asunto(s)
Relación Dosis-Respuesta en la Radiación , Células Madre Hematopoyéticas/efectos de la radiación , Leucemia Mielógena Crónica BCR-ABL Positiva/epidemiología , Leucemia Inducida por Radiación/epidemiología , Modelos Biológicos , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Recuento de Células , Transformación Celular Neoplásica/efectos de la radiación , Cromosomas Humanos Par 22/efectos de la radiación , Cromosomas Humanos Par 9/efectos de la radiación , Genes abl/efectos de la radiación , Humanos , Incidencia , Leucemia Mielógena Crónica BCR-ABL Positiva/etiología , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Inducida por Radiación/etiología , Leucemia Inducida por Radiación/patología , Persona de Mediana Edad , Cromosoma Filadelfia , Probabilidad , Tolerancia a Radiación , RiesgoRESUMEN
Using dual-color fluorescence in situ hybridization (FISH) combined with two-dimensional (2D) image analysis, the locations of ABL and BCR genes in cell nuclei were studied. The center of nucleus-to-gene and mutual distances of ABL and BCR genes in interphase nuclei of nonstimulated and stimulated lymphocytes as well as in lymphocytes stimulated after irradiation were determined. We found that, after stimulation, the ABL and BCR genes move towards the membrane, their mutual distances increase, and the shortest distance between heterologous ABL and BCR genes increases. The distribution of the shortest distances between ABL and BCR genes in the G0 phase of lymphocytes corresponds to the theoretical distribution calculated by the Monte-Carlo simulation. Interestingly, the shortest ABL-BCR distances in G1 and S(G2) nuclei are greater in experiment as compared with theory. This result suggests the existence of a certain regularity in the gene arrangement in the G1 and S(G2) nuclei that keeps ABL and BCR genes at longer than random distances. On the other hand, in about 2% to 8% of lymphocytes, the ABL and BCR genes are very close to each other (the distance is less than approximately 0.2 to 0.3 microm). For comparison, we studied another pair of genes, c-MYC and IgH, that are critical for the induction of t(8;14) translocation that occurs in the Burkitt's lymphoma. We found that in about 8% of lymphocytes, c-MYC and IgH are very close to each other. Similar results were obtained for human fibroblasts. gamma-Radiation leads to substantial changes in the chromatin structure of stimulated lymphocytes: ABL and BCR genes are shifted to the nuclear center, and mutual ABL-BCR distances become much shorter in the G1 and S(G2) nuclei. Therefore, we hypothesize that the changes of chromatin structure in the irradiated lymphocytes might increase the probability of a translocation during G1 and S(G2) stages of the cell cycle. The fact that the genes involved in the t(8;14) translocation are also located close together in a certain fraction of cells substantiates the hypothesis that physical distance plays an important role in the processes leading to the translocations that are responsible for oncogenic transformation of cells.
Asunto(s)
Núcleo Celular/efectos de la radiación , Cromosomas Humanos Par 22/ultraestructura , Cromosomas Humanos Par 9/ultraestructura , Genes abl , Linfocitos/efectos de la radiación , Cromosoma Filadelfia , Ciclo Celular , Núcleo Celular/química , Núcleo Celular/ultraestructura , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 14/ultraestructura , Cromosomas Humanos Par 22/genética , Cromosomas Humanos Par 22/efectos de la radiación , Cromosomas Humanos Par 8/genética , Cromosomas Humanos Par 8/ultraestructura , Cromosomas Humanos Par 9/genética , Cromosomas Humanos Par 9/efectos de la radiación , Fibroblastos/química , Fibroblastos/efectos de la radiación , Fibroblastos/ultraestructura , Proteínas de Fusión bcr-abl/genética , Rayos gamma , Genes de Inmunoglobulinas , Genes myc , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Hibridación Fluorescente in Situ , Interfase , Linfocitos/química , Linfocitos/ultraestructura , Método de Montecarlo , Translocación GenéticaRESUMEN
La etiología de los meningiomas no está dilucidada. Las radiaciones son uno de los pocos factores etiológicos estudiados que pueden inducir el desarrollo de estos tumores, al provocar alteraciones en el brazo largo del cromosoma 22. Se presenta el caso de una paciente que a raíz de una osteomielitis crónica de la calota, fue irradiada en el cráneo, desarrollando 20 años más tarde múltiples meningiomas de la convexidad, que fueron resecados. Se comentan las características de los meningiomas inducidos por radiaciones, como son la multiplicidad, frecuente localización en la convexidad, tendencia a la malignización y recurrencia precoz, características que se deben tener en cuenta en el tratamiento