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Acquired Radioresistance of Hematopoietic Progenitors (Granulocyte/Monocyte Colony-Forming Units) During Chronic Radiation Leukemogenesis1

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Acquired Radioresistance of Hematopoietic Progenitors (Granulocyte/Monocyte Colony-Forming Units) During Chronic Radiation Leukemogenesis1 [CANCER RESEARCH 52, 1469-1476, March 15, 1992] Acquired Radioresistance of Hematopoietic Progenitors (Granulocyte/Monocyte Colony-forming Units) during Chronic Radiation Leukemogenesis1 Thomas M. Seed2 and Lillian V. Kaspar Biological and Medical Research Division, Argonne National Laboratory, Argonne, Illinois 60439-4833 ABSTRACT modulate the leukemic response of the individual and exposed population at large (3, 8-16). Radiologically, the more impor Protracted exposure of dogs to low daily doses of whole-body ir tant modulators include dose rate, cumulative dose, and dura radiation (7.5 cGy/day for duration of life) elicits a high incidence of tion of exposure; biologically, age, sex, immunohematopoietic myeloid leukemia or related myeloproliferative disorders. Under such exposure, vital hematopoietic progenitors [granulocyte/monocyte colony- competence, and genetic/oncogenetic makeup are clearly im forming units in agar (CFU-GM)] acquire increased radioresistance along portant but are not outweighed by factor(s) that selectively control and alter hematopoietic function either during or fol with renewed proliferative capacity at an early phase of evolving myeloid lowing radiation exposure. One such factor is the "repair com leukemia. To further characterize the expression of acquired radioresist ance by CFU-GM, we evaluated the effects of various exposure rates, petence" of the hematopoietic organ against radiation damage. cumulative radiation doses, and times of exposure and postexposure in In our work with a canine model of chronic radiation-induced several groups of long-lived dogs under two conditions of irradiation: (a) myeloid leukemia, we have identified a myeloid leukemia-prone continuous, duration-of-life exposures at dose rates of 0.3-7.5 cGy/day; phenotype, of which the characteristic hallmark is a hemato and (b) discontinuous, fraction-of-life exposures at dose rates of 3.8-26.3 poietic system (specifically, hematopoietic progenitors) that has cGy/day, with cumulative doses of 450-3458 cGy and postexposure times of 14-4702 days. Results indicated that (a) under protracted continuous acquired increased but aberrant repair capacities along with renewed proliferative capacity (11, 12, 17-19). It would seem irradiation, the degree of radioresistance expressed by CFU-GM in vitro increased markedly in a biphasic pattern with rising daily rates of reasonable that the induction of these preleukemic hemato exposure; (b) under discontinuous, fraction-of-life exposure regimens, poietic changes within susceptible animals under chronic irra elevated levels of radioresistance were expressed and stably maintained diation would be dictated by the same factors that control the by CFU-GM only following large radiation doses accumulated at high expression of overt leukemic disease (e.g., dose rate, total dose, dose rates; and (c) with extended postexposure times, the magnitude of etc.). expressed radioresistance appeared to wane. These results continue to The intent of this study, therefore, is to characterize the support the hypothesis that the acquisition of radioresistance and asso expression of acquired, repair-mediated radioresistance by vital ciated repair functions by vital lineage-committed progenitors, under the hematopoietic progenitors (CFU-GM)3 within chronically ir strong selective and mutagenic pressure of chronic irradiation, is tied radiated dogs, as modulated by (a) rate of exposure, (b) cumu temporally and causally to leukemogenic transformation elicited by ra lative dose, and (c) times of exposure and postexposure. diation exposure. MATERIALS AND METHODS INTRODUCTION Animals. Outbred beagles were derived from the closed Argonne Under appropriate exposure conditions, ionizing radiation National Laboratory colony; their status, origin, and general manage can act as a potent leukemogen, both in animals and in humans ment have been described (20). A total of 105 beagles were used in this (1-3). In the classic radiation leukemogenesis studies by Upton study: 34 (28 males, 6 females) served as nonirradiated controls, while et al. (4-6), the leukemogenic potential of a standard dose of the remaining 71 (60 males, 11 females) served as irradiated test ionizing radiation was shown to be markedly different when the animals. All dogs were anatomically and physiologically normal and in dose was delivered either acutely (in large single doses) or good health prior to entry into the experiment(s). These animals were part of larger groups under general toxicological evaluation of the long- chronically (in small daily doses over an extended period). At a term effects of chronic, low-dose irradiation. Various hematopathol- total exposure dose of 300 cGy, for example, acute exposures ogical aspects of the latter work, including interim survival and leuke were demonstrated to be 3-fold more effective than chronic mia patterns, have been reported (8-13,15-19,21-27). These extended exposures in inducing myeloid leukemia in RF male mice (3). The "response-sparing" (in this case, leukemia-sparing) effect animal groups comprised 1079 animals (292 nonirradiated control animals and 787 chronically irradiated animals, of which 369 received of protracting the course of exposure is commonly attributed continuous radiation exposures and the remaining 418 received frac to time-dependent repair of radiation-induced damage, regard tionated exposures). These extended animal groups were used in this less of whether the damage is prelethal, premutational, or study for the sole purpose of developing and illustrating leukemic pretransformational in nature (7). incidence rates under various regimens of chronic radiation exposure. From these and related studies, as well as from work in our Animal Irradiation. All irradiated dogs were housed in standard-size own laboratory with canines and chronic radiation exposure, it fiberglass cages just prior to (approximately 2 weeks) and throughout is clear that numerous radiological and biological variables the course of exposure. All experimental procedures, including the initiation of chronic radiation exposure (designated as day 0), were begun when the animals reached young adulthood (i.e., about 400-500 Received 9/13/91; accepted 1/8/92. The costs of publication of this article were defrayed in pan by the payment days of age). Dogs receiving a preset total dose of irradiation (i.e., of page charges. This article must therefore be hereby marked advertisement in discontinuous, fraction-of-life exposures) were maintained during the accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1This work was supported by the U.S. Department of Energy, Office of Health postirradiation period in wire pens. Control animals were caged simi and Environmental Research, under Contract W-31-109-ENG-38 and by U.S. larly. Irradiations were carried out in specially designed live-in exposure Department of Health and Human Services Interagency Agreement Y01-CP- 50503. 3The abbreviations used are: CFU-GM, granulocyte/monocyte colony-form *To whom all requests for reprints should be addressed, at Radiation Hema- ing unit in agar; GM, granulocyte/monocyte; ML, myeloid leukemia; MPD, tology Group, Biological and Medical Research Division (B1M/202), Argonne myeloproliferative disorders; SLD, sublethal damage; !>„.doseestimate to reduce National Laboratory, 9700 South Cass Avenue, Argonne, IL 60439-4833. cell survival by e'1; D,, dose estimate to reduce cell survival below 100%. 1469 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1992 American Association for Cancer Research. ACQUIRED RADIORESISTANCEOF CFU-GM Table 1 Test groups, number and sex of animals, number of marrows sampled, and radiobiological and temporal variables range No. marrows at start Age at testing" at testing rate time* dogsSex(M/F)No. sampledAge (days)" (days)Test(days)Age (days)Dose (cGy)Total dose°(cGy)Exposuretime^days)Postexposure exposures26766624'20/67/06/05/15/117/78586911»19"484 Group I. Continuous duration-of-life 101400± ±5134111 1400± ±3163943 952657+ ±3173543 ±0466 2022505± 1523805± 2022024± 117474± 9531846± 20245096± 10771359± 46499± 5021143± 1884922±2 583656+ ±1031081409000000Test±390401-34703650-43993781-43371447-35381369-2694393-18400.000.300.751.883.757.5001113±306903710 ± exposuresg22242222228/02/01/12/04/02/02/02/02/01/12/01822242142222403Group II. Discontinuous fraction-of-life 10407± 15584313± 10412± ±974792 873980± 1452± 1124502± 1133990± 17426± 1554841± 1724276± 12558± 5424941± 5524183± 90432± 6451039± ±735300 ±4475 3754650± 3244140± 11426+ 14749±1 ±04241 47400± 1763836± 1293318± ±0400 04192± ±03775 ±02309 ±74864-50804244-43814712-48714392-46114032-51494485-5387406-17734642-46574624-487338364140-42440.003.753.757.507.507.507.5012.7512.7512.7526.25045015004501050150034584501050150045001204006014020046135821181703786±73 " Average values + SD. * One sample (1/11) excluded from final analyses due to unacceptably low progenitor plating efficiency. ' Three animals (3/24) excluded from final group due to poor marrow/progenitor yields. "*Eleven samples (11/79) excluded from final analyses due to unacceptably low progenitor plating efficiencies. facilities equipped with attenuated MCo -y-ray sources (Gamma Beam The cloning method uses a "feeder" layer [containing IO6 buffy coat Irradiatoâ„¢, Atomic Energy of Canada, Ltd., Ottawa). Daily absorbed leukocytes from control donor dogs and 10% pooled plasma from doses were estimated to be 75% of the delivered air
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