Acquired radioresistance of hematopoietic progenitors (granulocyte/monocyte colony-forming units) during chronic radiation leukemogenesis.

ABSTRACT

Protracted exposure of dogs to low daily doses of whole-body gamma-radiation (7.5 cGy/day for duration of life) elicits a high incidence of myeloid leukemia or related myeloproliferative disorders. Under such exposure, vital hematopoietic progenitors [granulocyte/monocyte colony-forming units in agar (CFU-GM)] acquire increased radioresistance along with renewed proliferative capacity at an early phase of evolving myeloid leukemia. To further characterize the expression of acquired radioresistance by CFU-GM, we evaluated the effects of various exposure rates, cumulative radiation doses, and times of exposure and postexposure in several groups of long-lived dogs under two conditions of irradiation (a) continuous, duration-of-life exposures at dose rates of 0.3-7.5 cGy/day; and (b) discontinuous, fraction-of-life exposures at dose rates of 3.8-26.3 cGy/day, with cumulative doses of 450-3458 cGy and postexposure times of 14-4702 days. Results indicated that (a) under protracted continuous irradiation, the degree of radioresistance expressed by CFU-GM in vitro increased markedly in a biphasic pattern with rising daily rates of exposure; (b) under discontinuous, fraction-of-life exposure regimens, elevated levels of radioresistance were expressed and stably maintained by CFU-GM only following large radiation doses accumulated at high dose rates; and (c) with extended postexposure times, the magnitude of expressed radioresistance appeared to wane. These results continue to support the hypothesis that the acquisition of radioresistance and associated repair functions by vital lineage-committed progenitors, under the strong selective and mutagenic pressure of chronic irradiation, is tied temporally and causally to leukemogenic transformation elicited by radiation exposure.