Chromosome aberrations and transforming genes in leukemic and non-leukemic patients with a history of atomic bomb exposure

To investigate leukemogenesis in atomic bomb (A-bomb) survivors, chromosome aberrations in bone marrow cells, and T- and B-lymphocytes from 135 healthy persons who had been exposed within 1,000 m of the hypocenter of the Hiroshima A-bomb were sequentially examined. Leukemic marrow cells from 468 patients with acute or chronic type of leukemias, including 25 acute leukemias exposed to 1 rad or more of radiation were also studied cytogenetically. Analysis of breakpoints observed in T-lymphocytes with stable types of abnormalities revealed a nonrandom distribution, and clustering in specific regions of chromosomes such as 22q1, 14q3, and 5q3. Statistical analysis revealed a higher incidence of translocations in 50 bands, including those containing cellular oncogenes such as 8q22, 8q24, and 9q34. Of these 50 bands, 20 were matched with bands specific for leukemia and cancer and 14 with constitutive fragile sites. In leukemic marrow, all 10 patients who had been exposed to radiation of more than 200 rad and then developed acute non-lymphocytic leukemia had chromosome aberrations. Their aberrations were more complex than those in patients exposed to less than 200 rad (33 patients) and in the non-exposed patients (134 patients). DNA samples extracted from bone marrow cells of 13 survivors, including 4 healthy survivors with more than 30% chromosome abnormalities in the bone marrow and 9 leukemia patients were used for in vivo selection assay of transforming genes. Tumor formation in nude mice was observed in 3 of the 4 healthy survivors and 9 leukemia patients. All of the transfectants were shown to contain Alu sequences. The transforming N-ras gene was detected for the first time in the bone marrow cells from 3 heavily exposed survivors and from 7 leukemia patients with a history of radiation exposure.