H-ferritin overexpression promotes radiation-induced leukemia/lymphoma in mice.

H-ferritin (HF) is a core subunit of the iron storage protein ferritin and is related to the pathogenesis of malignant diseases. HF overexpression is present in human hematologic malignancies, suggesting that HF overexpression may contribute to the development of hematologic cancers. However, in vivo evidence that HF is directly linked to hematologic tumorigenesis has not yet been shown. In this study, we show that transgenic (tg) mice overexpressing the human HF gene (hHF-tg) developed aggressive radiation-induced thymic lymphoma/leukemia (TL) compared with wild-type (WT) mice, providing evidence that HF overexpression promotes leukemia/lymphomagenesis. Fractionated X-irradiation of hHF-tg mice caused a higher incidence and earlier onset of TL compared with WT mice. Immunological and pathological features of TLs were similar in both groups. However, proliferative activity of hHF-tg lymphoma cells was higher than that of WT lymphoma cells, and microarray analyses revealed that some leukemia/lymphoma-related genes were differentially expressed in hHF-tg TLs compared with WT TLs. To investigate whether cell damage induced by irradiation is related to leukemia/lymphomagenesis, we evaluated apoptotic levels in the thymus and bone marrow (BM) of hHF-tg and WT groups after fractionated X-irradiation. Apoptosis was augmented in the hHF-tg BM, but not in the thymus, compared with the WT BM, suggesting a possible linkage between increased BM apoptosis by HF overexpression and accelerated radiation-induced TL development. Our findings indicate that HF overexpression is closely related to the development of leukemia/lymphoma, which could have implications for the prevention of malignant hematologic diseases.

Environmental radon exposure and childhood leukemia.

Despite the fact that animal and human epidemiological studies confirmed a link between radon exposure in homes and increased risk of lung cancer in general population, other types of cancers induced by radon, such as leukemia, have not been consistently demonstrated. The aim of this review was to summarize data published thus far from ecological and case-control studies in exposed populations, taking into account radon dose estimation and evidence of radon-induced genotoxicity, in an effort to clarify the correlation between home radon exposure and incidence of childhood leukemia. Among 12 ecological studies, 11 reported a positive association between radon levels and elevated frequency of childhood leukemia, with 8 being significant. In conjunction with ecological studies, several case-control studies on indoor radon exposure and childhood leukemia were examined, and most investigations indicated a weak association with only a few showing significance. A major source of uncertainty in radon risk assessment is radon dose estimate. Methods for radon exposure measurement in homes of children are one of the factors that affect the risk estimates in a case-control study. The effects of radon-induced genetic damage were studied both in vitro and in vivo using genetic endpoints including chromosomal aberration (CA), micronuclei (MN) formation, gene mutation, and deletions and insertions. By applying a meta-analysis, an increased risk of childhood leukemia induced by indoor radon exposure was noted for overall leukemia and for acute lymphoblastic leukemia (ALL). Data thus indicated an association between environmental radon exposure and elevated leukemia incidence, but more evidence is required in both human investigations and animal mechanistic research before this assumption may be confirmed with certainty.

NUP98-HOXA9-transgenic zebrafish develop a myeloproliferative neoplasm and provide new insight into mechanisms of myeloid leukaemogenesis.

NUP98-HOXA9 [t(7;11) (p15;p15)] is associated with inferior prognosis in de novo and treatment-related acute myeloid leukaemia (AML) and contributes to blast crisis in chronic myeloid leukaemia (CML). We have engineered an inducible transgenic zebrafish harbouring human NUP98-HOXA9 under the zebrafish spi1(pu.1) promoter. NUP98-HOXA9 perturbed zebrafish embryonic haematopoiesis, with upregulated spi1 expression at the expense of gata1a. Markers associated with more differentiated myeloid cells, lcp1, lyz, and mpx were also elevated, but to a lesser extent than spi1, suggesting differentiation of early myeloid progenitors may be impaired by NUP98-HOXA9. Following irradiation, NUP98-HOXA9-expressing embryos showed increased numbers of cells in G2-M transition compared to controls and absence of a normal apoptotic response, which may result from an upregulation of bcl2. These data suggest NUP98-HOXA9-induced oncogenesis may result from a combination of defects in haematopoiesis and an aberrant response to DNA damage. Importantly, 23% of adult NUP98-HOXA9-transgenic fish developed a myeloproliferative neoplasm (MPN) at 19-23 months of age. In summary, we have identified an embryonic haematopoietic phenotype in a transgenic zebrafish line that subsequently develops MPN. This tool provides a unique opportunity for high-throughput in vivo chemical modifier screens to identify novel therapeutic agents in high risk AML.

Murine models of human acute myeloid leukemia.

Primary human AML cells can be isolated and studied in vitro, but many experimental questions can only be addressed using in vivo models. In particular, tractable animal models are needed to test novel therapies. The genetic complexity of human AML poses significant challenges for the generation of reliable animal models. The hematopoietic systems of both zebrafish ( Danio rerio) and Drosophila have been well characterized ( reviewed in [5, 31]) . Both organisms are well suited to forward genetics mutagenesis screens. Although this approach has been useful for identification of mutants with hematopoietic phenotypes ( e.g., cloche), the impact on cancer biology and hematopoietic malignancies in particular has been limited. A zebrafish model of acute lymphoblastic leukemia has been generated [37] and Drosophila models have shed light on the biology of epithelial tumors ( reviewed in [60]). Nonetheless, in vivo modeling of human AML relies most heavily on mice. Most cellular, molecular, and developmental features of the hematopoietic system are well conserved across mammalian species. The availability of the human and mouse genome sequences and the capability of manipulating the mouse genome make mice the most valuable model organism for AML research. Mice have additional practical value because they have a short reproductive cycle and are relatively inexpensive to house.

[The influence of ferromagnetic screening from natural electromagnetic fields on the hematological and toxicogenomic indexes in animals].

The aim of the study was to reveal during 45 days consequences of ferromagnetic screening (FS) on the hematological and toxicogenomic indexes in rats. An express-method of nucleiod DNA content in blood by help fluorescent indication was used for alive quantitative evaluation of the toxicogenomic effects. The FS for both gender rats during 48 hrs resulted in both decreased magnetic field by 4-10 microT1 and leucopenia by 14 day of experiment. The aneu-/polyploidy index in male leucocytes was increased by 48 hr of FS and lasted out to 12-28 days after the screen removal. The leukocyte apoptosis was enhanced in female in 48 hrs only after the FS start.

Gorlin-Goltz syndrome and neoplasms: a case study.

UNLABELLED: Gorlin syndrome is a rare autosomal dominant disorder exhibiting high penetrance and variable expressivity. It is characterized by facial dysmorphism, skeletal anomalies, multiple basal cell carcinomas, odontogenic keratocysts (OKC), palmar and plantar pits, bifid ribs, vertebral anomalies and a variety of other malformations. Various neoplasms, such as medulloblastomas, meningiomas, ovarian and cardiac fibromas are also found in this syndrome. OBJECTIVE: To describe a twelve-year-old patient with Gorlin-Goltz syndrome, with basal cell carcinomas and promyelocytic leukemia developed after receiving craniospinal radiation for a medulloblastoma. Bifid ribs as well as mandibular and maxillar OKC were also diagnosed Conclusion: The patient with Gorlin-Goltz syndrome should receive close follow-up for early detection of malformations nd malignant neoplasias.

Implication of replicative stress-related stem cell ageing in radiation-induced murine leukaemia.

BACKGROUND: The essential aetiology of radiation-induced acute myeloid leukaemia (AML) in mice is the downregulation of the transcription factor PU.1. The causative mutation of the PU.1-endocing Sfpi1 gene consists mostly of C:G to T:A transitions at a CpG site and is likely to be of spontaneous origin. To work out a mechanism underlying the association between radiation exposure and the AML induction, we have hypothesised that replicative stress after irradiation accelerates the ageing of haematopoietic stem cells (HSCs), and the ageing-related decline in DNA repair could affect the spontaneous mutation rates. METHODS: Mathematical model analysis was conducted to examine whether and to what extent the cell kinetics of HSCs can be modified after irradiation. The haematopoietic differentiation process is expressed as a mathematical model and the cell-kinetics parameters were estimated by fitting the simulation result to the assay data. RESULTS: The analysis revealed that HSCs cycle vigourously for more than a few months after irradiation. The estimated number of cell divisions per surviving HSC in 3 Gy-exposed mice reached as high as ten times that of the unexposed. INTERPRETATION: The mitotic load after 3 Gy irradiation seems to be heavy enough to accelerate the ageing of HSCs and the hypothesis reasonably explains the leukaemogenic process.

Acute promyelocytic leukemia after whole brain irradiation of primary brain lymphoma in an HIV-infected patient.

The occurrence of acute promyelocytic leukemia (APL) in HIV-infected patients has been reported in only five cases. Due to a very small number of reported HIV/APL patients who have been treated with different therapies with the variable outcome, the prognosis of APL in the setting of the HIV-infection is unclear. Here, we report a case of an HIV-patient who developed APL and upon treatment entered a complete remission. A 25-years old male patient was diagnosed with HIV-infection in 1996, but remained untreated. In 2004, the patient was diagnosed with primary central nervous system lymphoma. We treated the patient with antiretroviral therapy and whole-brain irradiation, resulting in complete remission of the lymphoma. In 2006, prompted by a sudden neutropenia, we carried out a set of diagnostic procedures, revealing APL. Induction therapy consisted of standard treatment with all-trans-retinoic-acid (ATRA) and idarubicin. Subsequent cytological and molecular ana?lysis of bone marrow demonstrated complete hematological and molecular remission. Due to the poor general condition, consolidation treatment with ATRA was given in March and April 2007. The last follow-up 14 months later, showed sustained molecular APL remission. In conclusion, we demonstrated that a complete molecular APL remission in an HIV-patient was achieved by using reduced-intensity treatment.

RADIATION-INDUCED BYSTANDER EFFECT - MODELING, MANIFESTATION, MECHANISMS, PERSISTENCE, CANCER RISKS (literature review). / RADIATsIY̆NO-INDUKOVANYY̆ EFEKT SVIDKA ­ MODELIuVANNIa, PROIaVY, MEKhANIZMY ROZVYTKU, PERSYSTENTsIIa, ONKOLOGIChNI RYZYKY (ogliad literatury).

The review summarizes and analyzes the data of world scientific literature and the results of the own research con- cerning one of the main non-targeted effects of ionizing radiation - the radiation induced bystander effect (RIBE) - the ability of irradiated target cells to induce secondary biological changes in non-irradiated receptor cells. The his- tory of studies of this phenomenon is presented - it described under various names since 1905, began to study from the end of the twentieth century when named as RIBE and caused particular interest in the scientific community during recent decades. It is shown that the development of biological science and the improvement of research methods allowed to get new in-depth data on the development of RIBE not only at the level of the whole organism, but even at the genome level. The review highlights the key points of numerous RIBE investigations including mod- eling; methodological approaches to studying; classification; features of interaction between irradiated and intact cells; the role of the immune system, oxidative stress, cytogenetic disorders, changes in gene expression in the mechanism of development of RIBE; rescue effect, abscopal effect, persistence, modification, medical effects. It is emphasized that despite the considerable amount of research concerning the bystander response as the universal phenomenon and RIBE as one of its manifestations, there are still enough «white spots¼ in determining the mech- anisms of the RIBE formation and assessing the possible consequences of its development for human health.

Implications of hemopoietic progenitor cell kinetics and experimental leukemogenesis: Relevance to Gompertzean mortality as possible hematotoxicological endpoint.

OBJECTIVE: The aim of this study is to investigate a possible implication in cell kinetics of the hematopoietic progenitors to the experimental leukemogenesis to elucidate the relevance of various leukemic mode of action to Gompertzean survival curves, a new parameter based on the lifespan. MATERIALS AND METHODS: Mice, C3H/He, and C57BL/6 strain, male and female, with or without genetic modifications, e.g., p53-deficiency or thioredoxin overexpression were used in the present hemopoietic stem/progenitor research, radiation- or benzene-induced leukemogenesis followed by histopathological examination. A lethal dose of radiation for bone marrow transplantation, and a graded increased dose up to 5 Gy of x-rays for induction of hematopoietic malignancies were given. For caloric restriction studies, 77 kcal/week was maintained in accordance to different restriction-timing. For assays of hematopoietic colonization, colony-forming unit spleen and colony-forming unit granulocyte macrophage were evaluated. Hematopoietic progenitor cell-specific kinetics were studied by continuous labeling of bromodeoxyuridine for cycling cells, followed by ultraviolet (UV) exposure and hemopoietic colonization (bromodeoxyuridine UV [BUUV] method). Various experimental survival curves were applied to a mathematical analysis by Gompertz-Makeham law of mortality. RESULTS: Referring current authors' studies on leukemogenesis induced by ionizing radiation and benzene exposure, implications of hematopoietic progenitor cell kinetics to the experimental leukemogenesis were evaluated by means of a novel experimental tool, the BUUV method. Comparative studies to elucidate relevancies of these data, including two prevention studies, one on caloric restriction and the other on antioxidative thioredoxin overexpression, to those Gompertzean survival curves of experimental animals were analyzed. CONCLUSION: The Gompertzean expression may elucidate an appropriate toxicological endpoint for evaluating the effect of radiation and/or benzene-exposure on the lifespan and its modification by various experimental preventive measures.

Expression changes of ERK1/2, STAT3 and SHP-2 in bone marrow cells from gamma-ray induced leukemia mice.

The aim is to clarify expression changes of ERK1/2, STAT3 and SHP-2 in bone marrow cells from gamma-ray induced leukemia mice. A mouse model of gamma-ray induced leukemia was produced, and by means of quantitative real-time PCR, immunoprecipitation, Western blotting and electrophoretic mobility shift assays (EMSA), the expression of mRNA and protein, phosphorylation level, and protein activity of ERK1/2, STAT3 and SHP-2 in bone marrow cells were investigated in these mice. The results indicated that mRNA and protein expressions of ERK1/2 were upregulated, with significant increase of phosphorylation level and protein activity, but with insignificant differences in mRNA and protein expressions, phosphorylation level and protein activity of STAT3 and SHP-2 in bone marrow cells from gamma-ray induced leukemia mice compared to the radiation/tumor-free or control mice. It is concluded that in the pathogenesis of gamma-ray induced leukemia in Balb/C mice, activated ERK1/2 pathway may play a role, without involving STAT3 pathway; meanwhile, SHP-2 exerts no regulative effect on pathways of Ras-ERK1/2 and JAK-STAT.

Spontaneous and induced preleukemia cells in C57BL/6 mice:brief communication.

A transplantation bioassay method was used to verify the presence of preleukemia cells in C57BL/6 mice shortly after leukemogenic treatment or in relation to age increase. Preleukemia cells were identified mainly among bone marrow cells of old C57BL/6 mice or within 10 to 30 days after leukemogenic treatment of young mice with radiation-induced leukemia virus variants, fractionated doses of irradiation, or 7,12-dimethylbenz[a]anthracene (DMBA), although the overt disease did not occur until many months later. Mice could carry preleukemia cells without necessarily developing overt leukemia. Since the leukemogenic agents used in the present studies induced T-leukemias, the role of the thymus in the induction of preleukemia cells was tested. Thymectomy affected viral transformation but did not diminish the number of preleukemia cells induced by DMBA or X-ray.

Dose-response relationship of radiation-induced harderian gland tumors and myeloid leukemia of the CBA/Cne mouse.

Transplantation of harderian gland cells from CBA/-Cne mice into the fat pad of isogenic recipients was used for a quantitative in vivo study of cell survival and risk of transformation after x-ray irradiation (1-7 Gy). A survival curve for gland cells was generated in vivo with a D0 of 1.83 Gy and an extrapolation number of 7.23. Subsequently, the dose-response curve for lesions observed in nodules after cell transplantation was compared with that for lesions observed in glands irradiated in situ. A high incidence of epithelial hyperplasias with severe dysplasia was observed in transplantation nodules after x-irradiation. Gland tumors were significantly induced in whole-body irradiated animals; the tumors reached a maximum incidence after doses of 3 Gy. The risk of transformation per surviving cell was estimated both for dysplastic lesions and for tumors. These results approximated a dose-squared relationship in both cases, suggesting a common induction mechanism at the cellular level. Myeloid leukemia was observed at all doses in whole-body irradiated mice, and the maximum tumor incidence was reached at doses around 3 Gy.

Marrow-thymus interactions during radiation leukemogenesis in C57BL/Ka mice.

Transplantation of thymus and bone marrow cells from irradiated C57BL/Ka mice demonstrated the presence of potentially neoplastic cells in the thymus at 30 to 60 days postirradiation. During the same interval, no such cells could be detected in the bone marrow; moreover, the capacity of bone marrow cells to repopulate the thymus was impaired severely. These observations suggest that the primary site of neoplastic transformation in irradiated C57BL/Ka mice is the thymus rather than the bone marrow and that impaired thymic regeneration is a critical step in radiation leukemogenesis in mice.

Quantitation, in vitro propagation, and characterization of preleukemic cells induced by radiation leukemia virus.

Intrathymic (i.t.) inoculation of radiation leukemia virus into C57BL/6 mice induces a population of preleukemic (PL) cells that can progress into mature thymic lymphomas upon transfer into syngeneic recipients. A minimum of 10(3) PL thymic cells are required to induce lymphomas in the recipient. Most of the individual lymphomas developed in mice which were inoculated with cells of a single PL thymus, derived from different T-cell precursors. PL thymic cells could be grown in vitro on a feeder layer consisting of splenic stromal cells. Growth medium was supplemented with supernatant harvested from an established radiation leukemia virus-induced lymphoma cell line (SR4). The in vitro-grown PL cells were characterized as Thy-1+, CD4+, CD8- T-cells, most of which expressed radiation leukemia virus antigens. Cultured PL cells were found to be nontumorigenic, based on their inability to form s.c. tumors. However, these cells could develop into thymic lymphomas if inoculated i.t. into syngeneic recipients. A culture of PL cells, maintained for 2 mo, showed clonal T-cell receptor arrangement. Lymphomas which developed in several recipient mice upon injection with these PL cells were found to possess the same T-cell receptor arrangement. These results indicate that PL cells can be adapted for in vitro growth while maintaining their preleukemic character.

Induction of malignant transformation of cocultivated hematopoietic stem cells by X-irradiation of murine bone marrow stromal cells in vitro.

X-irradiation of purified primary cultures of mouse bone marrow stroma or permanent cloned marrow stromal cell lines in plateau phase decreases production of macrophage progenitor cell-specific colony-stimulating factor to a plateau minimum of 40% of control levels after doses of 50 to 500 Gy delivered at 2 Gy/min. After 50 Gy there is increased bioavailability of another growth factor(s) that is distinct from macrophage progenitor cell-specific colony-stimulating factor, granulocyte-macrophage progenitor cell colony-stimulating factor, or colony-stimulating factor for multipotential hematopoietic stem cells (interleukin 3). Liquid-phase cocultivation of irradiated stromal cells with either nonadherent cells from continuous marrow cultures or cloned dual granulocyte-macrophage progenitor cell colony-stimulating factor/interleukin 3-dependent hematopoietic progenitor cell lines induces evolution over 5 weeks of factor-independent colony-forming cells. Subcultured factor-independent colonies generated clonal malignant cell lines with multiple distinct karyotypic alterations. Inoculation of 10(6) cells s.c. from factor-independent clones into syngeneic mice produces local granulocytic monomyeloid tumors with spread to spleen, lymph nodes, and bone marrow. These data provide the first demonstration in vitro of indirect X-irradiation leukemogenesis through cells of the marrow stroma.

Leukemia in breast cancer patients following adjuvant chemotherapy or postoperative radiation: the NSABP experience.

Since 1971, 8,483 women with primary breast cancer participated in seven trials evaluating adjuvant chemotherapy. Leukemia occurred in only three of 2,068 patients treated by operation alone. The cumulative risk was 0.06% after 10 years in those free of metastases or a second primary tumor, and 0.27% in those with tumor. Thus, leukemia is not an important factor in the natural history of breast cancer. Five of 646 women receiving postoperative regional radiation developed leukemia, an overall risk of 1.39 +/- .49% at 10 years. Twenty-seven cases of leukemia (0.5%) and seven of myeloproliferative syndrome (0.1%) were recorded in 5,299 patients who received L-phenylalanine mustard (L-PAM)-containing regimens. The maximum cumulative risk of leukemia in chemotherapy recipients (leukemia of any type and myeloproliferative syndrome) was 1.68 +/- .33% at 10 years following operation. The risk excluding those with myeloproliferative syndrome was 1.29 +/- .28%. The risk of leukemia in patients free of metastases or a second primary was 1.11 +/- .30% at 10 years, and when combined with myeloproliferative syndrome, it was 1.54 +/- .36%; risks not significantly greater than observed following radiation (P = .58 and .29). No cases of leukemia were observed during the 2 years of chemotherapy and none have occurred after the seventh postoperative year. Comparisons with the surveillance, epidemiology, and end results tumor registries (SEER) data indicate an increased relative risk of acute myelogenous leukemia following postoperative regional radiation (P less than .01) and adjuvant chemotherapy (P less than .001). The findings indicate that hematologic disorders are side effects of both radiation and alkylating agents used in the adjuvant treatment of primary breast cancer. The risk of such events is lower than that reported following treatment of other solid tumors and hematologic malignancies by chemotherapy. The benefit from adjuvant chemotherapy for breast cancer exceeds the risk of leukemia. Since chemotherapy is not uniformly beneficial, efforts should be directed toward identifying responders so that only those who will benefit are exposed to the risk.

Absence of negative growth regulation in three new murine radiation-induced myeloid leukemia cell lines with deletion of chromosome 2.

Murine radiation-induced acute myeloid leukemia (RI-AML) may be considered as the experimental counterpart of human secondary leukemia. Three new myelomonocytic cell lines derived from RI-AML and carrying a partially deleted chromosome 2 are described. The RI-AML cells responded with increased proliferation after being incubated with the hemopoietic growth factors rG-CSF, rGM-CSF and IL-3. Increased proliferation of the same extent without any effect in differentiation, was also demonstrated in the RI-AML cells after incubation with IL-6 and with mouse lung conditioned medium (CM) and Krebs ascites tumor cells CM which induce differentiation in normal and most leukemic myeloid cells. Down-regulation of the c-myc gene and induction of (2'-5') oligo-adenylate synthetase (reflecting autocrine interferon secretion), two essential mechanisms operating during arrest of growth and concomitant differentiation, were demonstrated to be absent in RI-AML cells. In contrast, the M1 cells responded to the above differentiating factors with growth arrest and differentiation and with appropriate c-myc down-regulation and synthetase induction. The genetic basis for the distinct RI-AML cells' behavior may be connected with the loss or structural and/or functional abnormalities of DNA sequences located in the deleted part of chromosome 2 or in the respective allele. The presently described new RI-AML cell lines may be used for studies concerning myeloid leukemogenesis in general and secondary leukemia in particular.

Radiation-induced myeloid leukemia in mice under calorie restriction.

The host-defense mechanisms against cancers are known to be modulated by changing the environmental factor(s). The spontaneous incidence of myeloid leukemia is about 1% in C3H/He mice, and the incidence increases up to 23.3% when a single dose of radiation, 3 Gy X-ray, is exposed to a whole-body. Since calorie restriction was known to reduce the incidence of spontaneous tumors, a question as to whether such radiation induced-increase of myeloid leukemia would be also decreased by calorie restriction, was aimed to answer to elucidate possible mechanism of radiation-induced myeloid leukemia. By the calorie restriction, the incidence of myeloid leukemia was significantly decreased. In addition, the latent period of the myeloid leukemia in the groups for calorie restriction was significantly extended at a greater extent as compared with the control diet groups. Number of hemopoietic stem cells, the possible target cells for radiation-induced leukemias, in the groups for the calorie restriction demonstrated a significant decrease, especially in the spleen, as compared with that in the control, when the evaluation was made at the time of radiation exposure.

The p53-deficient hemopoietic stem cells: their resistance to radiation-apoptosis, but lasted transiently.

Hemopoietic stem cells lacking with p53 are known to be resistant to radiation apoptosis: p53-product induces, on one hand, the cells that have been injured by radiation to stop cell-cycle at G, phase, and on the other hand the cells that have not been repaired to go into apoptosis. Thus, in the p53-deficient mice, the hemopoietic stem cells after graded dose of radiation show a flatter survival curve for radiation, i.e., like a curve for radio-resistant phenotype. However, we found the radio-resistance in the stem cell was only transient, and an apoptosis in p53-deficient hemopoietic stem cells, we made concentrated analysis including the end-labeling technique to detect double strand breaks of DNA. Results clearly showed that, according to the end-labeling for spleen colonies, the p53-deficiency showed rather higher incidence of apoptosis (30-50%) as compared with the wild-control (17%). Irradiation with 200cGy for the recipient mice two months after transplantation, showed an induction of higher incidence of hemopoietic malignancies, when the heterozygous marrow was repopulated, however, none of increase was observed in the recipient mice repopulated with the homozygous bone marrow. Clear difference between the hetero- and the homozygous in inducing hemopoietic malignancies with the 200cGy-radiation may be reflected by the different degree of delayed appearance of apoptosis during the development of the spleen colonies.