HYPERMUTABILITY OF MOUSE CHROMOSOME-2 DURING THE DEVELOPMENT OF X-RAY-INDUCED MURINE MYELOID-LEUKEMIA

In an effort to identify the precise role of a deletion at regions D-E of mouse chromosome 2 [del2(D-E)] during the development of radiation -induced myeloid leukemia, we conducted a serial sacrifice study in wh ich metaphase chromosomes were examined by the G-banding technique. Su ch metaphase cells were collected from x-irradiated mice during the pe riod of transformation of some of the normal hematopoietic cells to th e fully developed leukemic phenotype. A group of 250 CBA/Ca male mice (10-12 weeks old) were exposed to a single dose of 2 Gy of 250-kilovol t-peak x-rays; 42 age-matched male mice served as controls. Groups of randomly selected mice were sacrificed at 20 hr, 1 week, and then at i ntervals of 3 months up to 24 months after x-irradiation. Slides for c ytogenetic, hematological, and histological examination were prepared for each animal at each sacrifice time. An expansion of cells with les ions on one copy of chromosome 2 was evident in 20-25% of treated mice at each sacrifice time. The majority of such lesions were translocati ons at 2F or 2H, strongly suggesting hypermutability of these sites on mouse chromosome 2. No lesions were found in control mice. The findin g leads to the possibility that genomic lesions close to 2D and 2E are aberrants associated with radiation leukemogenesis, whereas a single clone of cells with a del2(D-E) may lead directly to overt leukemia. T he data also indicate that leukemic transformation arises from the cum ulative effects of multiple genetic events on chromosome 2, reinforcin g the thesis that multiple steps of mutation occur in the pathogenesis of cancer.