Evidence for two commonly deleted regions on mouse chromosome 2 in gamma ray-induced acute myeloid leukemic cells.

Objective: The objective of this study was to delineate a precise molecular map of the commonly deleted region (CDR) on mouse chr2 in radiation-induced mouse acute myeloid leukemic (AML) cells.

Materials And Methods: We used a PCR-based loss of heterozygosity (LOH) assay to map the chr2-CDR in AML cells isolated from F1 hybrid mice (BALB/cJ x CBA/CaJ) which developed AML following exposure to a single dose of 3 Gy of 137Cs gamma rays. A total of 30 polymorphic microsatellite markers, mapping within or close to chr2(D-E), were used under optimized PCR conditions that generate a single major band for each marker on a nondenaturing polyacrylamide gel.

Telomerase activity in mouse myeloid leukemic cells and in cells from normal hematopoietic systems.

The telomeric repeat amplification protocol (TRAP) assay was used to measure telomerase activity in radiation-induced mouse myeloid leukemic (ML) cells and in several populations of normal cells. A detectable level of telomerase activity was found in normal hematopoietic tissues, i.e.

Characterization of genetic instability in radiation- and benzene-induced murine acute leukemia.

This study, using the CBA/Ca mouse as a model, compares genetic lesions associated with radiation- and benzene-induced acute leukemias. Specific types of leukemia included in the analyses are radiation-induced acute myeloid leukemia (ML), and benzene-induced lymphoblastic leukemias, lymphomas, or mix-lineage leukemias. These leukemias have histopathological characteristics similar to those seen in human acute leukemias.

Advantages of the CBA mouse in leukemogenesis research.

The objectives of this review are to: (a) demonstrate that the male CBA/Ca mouse has several characteristics that make it an excellent animal for the study of leukemogenesis, (b) show that several of the genetic abnormalities observed in the male CBA/Ca mouse during the development of radiation induced acute myeloid leukemia (AML) are syntenic with those frequently detected in patients with myeloid disorders such as myelodysplastic syndrome and AML, (c) illustrate that leukemia-related chromosomal lesions are the indicators for high risk individuals.

Historical events associated with fallout from Bravo Shot--Operation Castle and 25 Y of medical findings.

The events prior to Bravo Shot-Operation Castle that led to a decision not to evacuate the Marshallese prior to testing the thermonuclear bombs are presented as are the actions taken after the fallout incident in evacuating the exposed Marshallese and the military personnel. The initial medical effects (findings during first 6 wk after exposure) are briefly described and are followed by description of long term effects, namely, induction of one case of fatal acute myeloid leukemia and a large number of thyroid tumors (benign and malignant) in addition to hypothyroidism in adults and children and two cases of cretinism. The hypothyroidism and cretinism responded well to administration of oral thyroxine.

Lifetime treatment of mice with azidothymidine (AZT) produces myelodysplasia.

AZT has induced a macrocytic anemia in AIDS patients on long term AZT therapy. It is generally assumed that DNA elongation is stopped by the insertion of AZT into the chain in place of thymidine thus preventing the phosphate hydroxyl linkages and therefore suppresses hemopoietic progenitor cell proliferation in an early stage of differentiation. CBA/Ca male mice started on AZT 0.

Evidence for an uncommon microsatellite instability on mouse chromosomes 2 and 4 and its possible role in radiation leukemogenesis.

Although microsatellite instability (MSI), usually detected by DNA length polymorphisms, has been implicated in the induction of solid tumors in both humans and animals, its role in leukemogenesis is unclear. The goal of this study was to investigate whether there is an association between MSI and radiation leukemogenesis in CBA/Ca mice. Microsatellite lengths at 55 loci, mapped to eight different mouse chromosomes, were examined in two groups of DNA samples: 1) 10 normal DNA samples collected from the bone marrow cells of control male CBA/Ca mice, and 2) 17 DNA samples isolated from the spleens of mice that developed myeloid leukemia (ML) after exposure to neutrons, or X rays, or gamma rays.

Effects of irradiation of CBA/CA mice on hematopoietic stem cells and stromal cells in long-term bone marrow cultures.

Following 200 cGy total body irradiation, 20-25% of CBA/Ca mice and their CBA/B and CBA/H sublines develop myeloid leukemia. To determine whether hematologic changes in vitro were detectable, long-term marrow cultures (LTBMCs) were established from the right and left hind limbs of 11 individual control and 11 CBA/B mice 100-114 days after 200 cGy total body irradiation. Individual cultures were studied weekly for cumulative production of nonadherent cells and colony-forming, hematopoietic progenitor cells.

N-ras mutations in radiation-induced murine leukemic cells.

N-ras mutations were examined in DNA samples extracted from the spleen of CBA/Ca mice that developed myeloid leukemia (ML) following exposure to radiations of different qualities. A total of 17 ML cases, i.e.

Survival of spleen colony-forming units (CFU-S) of irradiated bone marrow cells in mice: evidence for the existence of a radioresistant subfraction.

Because of increasing evidence of heterogeneity in the hematopoietic stem cell compartments, the radiosensitivity of spleen colony-forming units (CFU-S) was reevaluated to ascertain whether the classical single exponential curve for a graded dose of radiation is applicable at higher doses of radiation, 400-600 cGy. Bone marrow cells (BMC) removed from mice immediately after death under anesthesia were irradiated in vitro. Great care was taken to exclude anoxic effects during irradiation and to avoid any possible effects in the recipient mice from injection of excessive numbers of BMC.

Medical effects of exposure of human beings to fallout radiation from a thermonuclear explosion.

On March 1, 1954, after detonation of a thermonuclear device on Bikini atoll, an unexpected wind shift resulted in the deposition of radioactive fallout on inhabited atolls. The fallout radiation caused fleeting systemic effects, dose-dependent depression of hematopoiesis and skin burns primarily due to the beta ray component of the fission radionuclides. Within a few weeks, hematopoietic recovery was substantial but slight depression of blood counts was maintained for several years.

Physiological and pathophysiological aspects of the immune system contributing to a biomathematical model of lymphocytes.

The effects of chronic low-dose irradiation on the immune system and the lymphocytes are largely unknown. The uranium miners in the former German Democratic Republic (GDR) were exposed mainly to a local low-dose irradiation in the lung by radon and its progeny, but also to some whole-body gamma irradiation. The local irradiation led to an increased rate of lung cancer and perhaps to some increase in extrapulmonary neoplasms.

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 which metaphase chromosomes were examined by the G-banding technique. Such metaphase cells were collected from x-irradiated mice during the period of transformation of some of the normal hematopoietic cells to the 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-kilovolt-peak x-rays; 42 age-matched male mice served as controls.

Influence of radiation fractionation on survival of mice and spleen colony-forming units.

C57Bl/6 mice were given 10 Gy X rays fractionated in several ways. There was a cyclical pattern of animal survival which was correlated to the fractionation interval and which indicated a periodicity of 6 h. Ten grays given in a single dose is fatal to 100% of the mice and depresses the CFU-S to about one per leg with no evidence of proliferation during the remaining life.

Partial amelioration of AZT-induced macrocytic anemia in the mouse by folic acid.

CBA/Ca mice being maintained on azidothymidine (AZT) in drinking water were given vitamin B12 and folate in an effort to ameliorate the macrocytic anemia associated with AZT administration. The B12/folate regimen was ineffectual, but higher doses of folate given daily resulted in an increase in RBC and a decrease in mean corpuscular hemoglobin (MCH) and polychromatophilic erythrocytes (PCE) while mean corpuscular volume (MCV) remained relatively constant. The implications of these findings on RBC production and hemoglobin synthesis are discussed.

Self-renewal of the long-term repopulating stem cell.

Self-renewal implies maintenance of all attributes of the original in the offspring and is considered characteristic of the hemopoietic stem cells. Yet, it has been questioned whether one of the most primitive hemopoietic stem cells, the long-term repopulating cell (LTRC), has that capacity. The present experiments demonstrate that single LTRCs can repopulate the lymphohemopoietic system of a lethally irradiated mouse and that the progeny of a single LTRC in a primary recipient again contains LTRCs capable of repopulating lethally irradiated secondary recipients.

Are stem cells exposed to ionizing radiation in vivo as effective as nonirradiated transfused stem cells in restoring hematopoiesis?

Are the stem cells that survive graded doses of ionizing radiation as effective in restoring hematopoiesis in irradiated mice as transfused nonirradiated stem cells? This question was addressed by determining animal dose mortality and 10-day colony-forming units (CFU-S) survival curves and then replotting the percent animal survival against the number of CFU-S surviving the different doses of radiation, and by determining the number of nonirradiated CFU-S injected into fatally irradiated mice that result in a CFU-S dose mortality response curve. The number of CFU-S surviving per mouse after doses of radiation resulting in 95, 50 and 5% animal survival were calculated to be 520, 300 and 153, respectively. From the transfused CFU-S dose mortality curve of otherwise fatally irradiated mice (8.

A specific chromosomal deletion in murine leukemic cells induced by radiation with different qualities.

G-banded metaphase chromosomes prepared from 14 male CBA/Ca mice with histologically confirmed myeloid leukemia (ML) were studied in an effort to identify specific chromosomal changes associated with radiation leukemogenesis. The chromosome studies were undertaken as part of a larger investigation of radiation carcinogenesis, in which mice were exposed to radiation of several different qualities, i.e.

Anemia induced in splenectomized mice by administration of rhG-CSF.

Normal and splenectomized mice (SPLXM) were given rhG-CSF for 10 to 128 days and serial observations were made on blood counts for 128 days. After 10 days, mice were killed for histologic studies. All treatment schedules produced, in addition to elevated white blood counts, a macrocytic anemia which only partially responded to large doses of Epo.

Competitive repopulation in leukemic and normal bone marrow.

The success of chemotherapy in leukemias in which the marrow appears entirely replaced by leukemic cells must be due to the persistence of some normal stem cells. The implied competition between leukemic and normal stem cells is thus akin to the competition between donor and host cells in irradiated animals. A review of that competition points to the importance of the quantitative relationships between the competing stem cells, even when one of the competing stem cell clones has a proliferative advantage.

In vivo toxicity of 3'-azido-3'-deoxythymidine (AZT) on CBA/Ca mice.

CBA/Ca male mice were given 3'-azido-3'-deoxythymidine (AZT) in drinking water (1 mg/ml) for up to 7 weeks. Water consumption and body weight decreased significantly. Neutropenia and lymphopenia were observed during and after exposure.

Is natural background or radiation from nuclear power plants leukemogenic?

In view of the enormous number of base pair replications per annum in hemopoietic stem cells with the likelihood of coding errors, the rarity of the leukemogenic event at the cellular level after high doses of radiation, the infrequent occurrence of radiation events in cells at low-level exposure (large fraction of cells uninvolved), biological protective mechanisms and the realization that exposure of human populations to radiation from nuclear power plants is a very small fraction of natural radioactivity and will for the foreseeable future remain small and that populations exposed to high natural background radiation show no detectable harmful effects, it is concluded that either there is no effect, or for statistical reasons one cannot detect an effect.