8-hydroxy-2--deoxyguanosine and Leukemia--Radiation-Induced

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.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Apoferritins; Apoptosis; Deoxyguanosine; Flow Cytometry; Humans; Leukemia, Radiation-Induced; Lymphoma; Mice; Mice, Inbred C57BL; Mice, Transgenic; Survival Rate; X-Rays

The evolution of mitochondrial oxidative phosphorylation was studied during cancer induction in a model of thymic radiolymphomagenesis in C57BL/Ka mice. During the preneoplastic period, thymuses displayed an increase of the cytochrome c oxidase activity and oxygen consumption together with oxidative DNA damage assessed by the presence of the 8-hydroxydeoxyguanine DNA base modification. These transient changes in mitochondrial functional activity were not observed in thymuses of mice rescued from lymphoma development by a bone marrow graft, suggesting an important role of mitochondria for neoplastic transformation in this model, which might therefore be of interest to test the utilization of antioxidants for the prevention of radiation-induced malignancies.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Bone Marrow Transplantation; Cell Respiration; Cell Transformation, Neoplastic; Deoxyguanosine; Electron Transport Complex IV; Female; Flow Cytometry; In Situ Hybridization; Leukemia, Radiation-Induced; Lymphoma; Male; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence; Oxidative Stress; Oxygen Consumption; Preleukemia; Thymus Gland; Thymus Neoplasms; Up-Regulation; Whole-Body Irradiation