title: Friend leukemia virus infection enhances DNA damage-induced apoptosis of hematopoietic cells, causing lethal anemia in C3H hosts.
abstract: Exposure of hematopoietic progenitors to gamma irradiation induces p53-dependent apoptosis. However, host responses to DNA damage are not uniform and can be modified by various factors. Here, we report that a split low-dose total-body irradiation (TBI) (1.5 Gy twice) to the host causes prominent apoptosis in bone marrow cells of Friend leukemia virus (FLV)-infected C3H mice but not in those of FLV-infected DBA mice. In C3H mice, the apoptosis occurs rapidly and progressively in erythroid cells, leading to lethal host anemia, although treatment with FLV alone or TBI alone induced minimal apoptosis in bone marrow cells. A marked accumulation of P53 protein was demonstrated in bone marrow cells from FLV-infected C3H mice 12 h after treatment with TBI. Although a similar accumulation of P53 was also observed in bone marrow cells from FLV-infected DBA mice treated with TBI, the amount appeared to be parallel to that of mice treated with TBI alone and was much lower than that of FLV- plus TBI-treated C3H mice. To determine the association of p53 with the prominent enhancement of apoptosis in FLV- plus TBI-treated C3H mice, p53 knockout mice of the C3H background (C3H p53(-/-)) were infected with FLV and treated with TBI. As expected, p53 knockout mice exhibited a very low frequency of apoptosis in the bone marrow after treatment with FLV plus TBI. Further, C3H p53(-/-) --> C3H p53(+/+) bone marrow chimeric mice treated with FLV plus TBI survived even longer than the chimeras treated with FLV alone. These findings indicate that infection with FLV strongly enhances radiation-induced apoptotic cell death of hematopoietic cells in host animals and that the apoptosis occurs through a p53-associated signaling pathway, although the response was not uniform in different host strains.
authors.affiliation: Department of Pathology and Immunology, Aging and Developmental Sciences, Division of Gerontology and Gerodontology, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8519, Japan. masa.pth2@med.tmd.ac.jp
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kitagawa
authors.forename: Shuichi
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Maki
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Kaoru
authors.initials: K
authors.lastname: Tanaka
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Sado
authors.forename: Katsuiku
authors.initials: K
authors.lastname: Hirokawa
authors.forename: Shiro
authors.initials: S
authors.lastname: Aizawa
mesh_terms: D000740:Anemia / Q000401:mortality*; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D001854:Bone Marrow Cells / Q000378:metabolism; D004249:DNA Damage; D005622:Friend murine leukemia virus / Q000472:pathogenicity*; D005720:Gamma Rays; D006412:Hematopoietic Stem Cells / Q000502:physiology / Q000528:radiation effects*; D007942:Leukemia, Experimental / Q000401:mortality / Q000532:radiotherapy; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D012192:Retroviridae Infections / Q000401:mortality / Q000532:radiotherapy; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology; D014412:Tumor Virus Infections / Q000401:mortality / Q000532:radiotherapy; D014916:Whole-Body Irradiation / Q000009:adverse effects
chemical_list: D016159:Tumor Suppressor Protein p53