Radiation-induced myeloid leukemia in C3H/He mice and the effect of prednisolone acetate on leukemogenesis

Division of Physiology and Pathology, National Institute of Radiological Sciences, Chiba, Japan.
Radiation Research (Impact Factor: 2.45). 09/1991; 127(2):146-9. DOI: 10.2307/3577958
Source: PubMed

ABSTRACT We found that the incidence of spontaneous myeloid leukemia in C3H/He male mice was less than 1%, but it could be increased considerably by total-body X irradiation. The induction of myeloid leukemia was seen to increase after doses from 0.47 Gy (3%) to 2.84 Gy (23.9%), and then decrease after a dose of 4.73 Gy (13.6%). The administration of prednisolone acetate (synthesized glucocorticoid) after irradiation resulted in a significant increase in the incidence of myeloid leukemia from 23.9 to 38.5% after a dose of 2.84 Gy; however, corticosterone, a glucocorticoid secreted by cells, did not have such an enhancing effect.

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    • "However, homozygous Trp53-deficient mice are difficult to utilize because of the high frequency of spontaneous thymic lymphomagenesis (Hirabayashi et al., 2003; MacDonald et al., 2004) due to the lack of physiological apoptosis in the double-negative immature T-cell subpopulation during the developmental stage (Haines et al., 2006). Because the C3H/He strain exhibits a relatively high incidence of AML (Seki et al., 1991; Yoshida et al., 1996), the use of Trp53-deficient mice from both the C57BL/6 strain and the C3H/He strain may elucidate potential relationships and differences between benzene exposure and the development of AMLs in these two strains. Owing to the high neoplastic sensitivity and myeloid leukemogenicity of the heterozygous Trp53-deficient C3H/He mice use in this study, exposure to benzene induced straindependent HPNs, including AMLs, in a nearly benzene dose– dependent manner, suggesting that our findings on the heterozygous Trp53-deficient mouse may provide a useful experimental model for studying benzene-induced hematotoxicity. "
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    ABSTRACT: This research focused on three major questions regarding benzene-induced hematopoietic neoplasms (HPNs). First, why are HPNs induced equivocally and at only threshold level with low-dose benzene exposure despite the significant genotoxicity of benzene even at low doses both in experiments and in epidemiology? Second, why is there no linear increase in incidence at high-dose exposure despite a lower acute toxicity (LD(50) > 1000 mg/kg body weight; WHO, 2003, Benzene in drinking-water. Background document for development of WHO Guidelines for Drinking-Water Quality)? Third, why are particular acute myeloid leukemias (AMLs) not commonly observed in mice, although AMLs are frequently observed in human cases of occupational exposure to benzene? In this study, we hypothesized that the threshold-like equivocal induction of HPNs at low-dose benzene exposure is based on DNA repair potential in wild-type mice and that the limited increase in HPNs at a high-dose exposure is due to excessive apoptosis in wild-type mice. To determine whether Trp53 deficiency satisfies the above hypotheses by eliminating or reducing DNA repair and by allowing cells to escape apoptosis, we evaluated the incidence of benzene-induced HPNs in Trp53-deficient C57BL/6 mice with specific regard to AMLs. We also used C3H/He mice, AML prone, with Trp53 deficiency to explore whether a higher incidence of AMLs on benzene exposure might explain the above human-murine differences. As a result, heterozygous Trp53-deficient mice of both strains showed a nonthreshold response of the incidence of HPNs at the lower dose, whereas both strains showed an increasing HPN incidence up to 100% with increasing benzene exposure dose, including AMLs, that developed 38% of heterozygous Trp53-deficient C3H/He mice compared to only 9% of wild-type mice exposed to the high dose. The detection of AMLs in heterozygous Trp53-deficient mice, even in the C57BL/6 strain, implies that benzene may be a potent inducer of AMLs also in mice with some strain differences.
    Toxicological Sciences 05/2009; 110(2):293-306. DOI:10.1093/toxsci/kfp107
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    • "Primary myeloid leukemia cells were induced in the C3H mice 1–2 years after whole-body X-irradiation at 3 Gy (Yoshida et al., 1986) and isolated from spleen. The myeloid leukemia lines L8002, L8028, L8065, and L-8072 (Ishihara et al., 2000) used in this study were established by in vivo passage of the primary leukemia cells more than five times (Hayata et al., 1983; Seki et al., 1991; Ishihara et al., 1993). They were prepared from the enlarged spleens of mice 2–4 weeks after intravenous injection of the leukemia cells. "
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    ABSTRACT: Cells of acute myeloid leukemia (AML) from C3H/He mice express an increased amount of RNA for an endogenous retrovirus-like retrotransposon, intracisternal A-particle element. We analyzed the transcription of other mouse retrotransposons in C3H-derived tumor cells and found that all the AML lines from different mice overexpress early-transposon (ETn) RNA. In contrast, only faint levels of ETn were detected in the cells from other tumors, including hepatoma and lymphoma. The polyadenylation sites of the ETn RNA in the AML cells varied. We also determined the binding site for the nuclear extract of the AML cells in the long terminal repeat sequence of ETn. The overexpression of ETn as a common phenotype of AML cells suggests that myeloid cells with this phenotype are the origin of all the AML cells or that the phenotype is acquired during leukemogenesis.
    Virology 03/2001; 280(1):107-14. DOI:10.1006/viro.2000.0732
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    ABSTRACT: C3H/He mice develop acute myeloid leukemia (AML) after whole-body irradiation, and typical chromosome 2 deletions are found in the leukemic cells. To investigate a process of the formation and the expansion of the AML-specific deletions, we have examined its frequency in primitive hematopoietic cells that could be the target of the leukemogenesis. Male C3H/He mice were exposed to 3Gy x-rays and sacrificed after certain periods of time. Bone marrow cells were collected from the femora and a single-cell suspension from each animal was divided into two parts. One part of the cell suspension was cultured in methylcellulose medium, and metaphase spreads were prepared from each growing colony. The other part was sorted to obtain Lin + and Lin – Sca1 + cells, and those cells were scored with FISH for the AML-specific deletions. Karyotyping of the cultured cells detected signs of the delayed chromosomal instability, but an aberration involving chromosome 2 has not been found so far. FISH to the sorted cells, however, revealed the AML-specific deletions could be produced in the primitive hematopoietic cells as an early event of radiation exposure.
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