title: Nature of nontargeted radiation effects observed during fractionated irradiation-induced thymic lymphomagenesis in mice.
abstract: Changes in the thymic microenvironment lead to radiation-induced thymic lymphomagenesis, but the phenomena are not fully understood. Here we show that radiation-induced chromosomal instability and bystander effects occur in thymocytes and are involved in lymphomagenesis in C57BL/6 mice that have been irradiated four times with 1.8-Gy γ-rays. Reactive oxygen species (ROS) were generated in descendants of irradiated thymocytes during recovery from radiation-induced thymic atrophy. Concomitantly, descendants of irradiated thymocytes manifested DNA lesions as revealed by γ-H2AX foci, chromosomal instability, aneuploidy with trisomy 15 and bystander effects on chromosomal aberration induction in co-cultured ROS-sensitive mutant cells, suggesting that the delayed generation of ROS is a primary cause of these phenomena. Abolishing the bystander effect of post-irradiation thymocytes by superoxide dismutase and catalase supports ROS involvement. Chromosomal instability in thymocytes resulted in the generation of abnormal cell clones bearing trisomy 15 and aberrant karyotypes in the thymus. The emergence of thymic lymphomas from the thymocyte population containing abnormal cell clones indicated that clones with trisomy 15 and altered karyotypes were prelymphoma cells with the potential to develop into thymic lymphomas. The oncogene Notch1 was rearranged after the prelymphoma cells were established. Thus, delayed nontargeted radiation effects drive thymic lymphomagenesis through the induction of characteristic changes in intrathymic immature T cells and the generation of prelymphoma cells.
authors.affiliation: Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan. tsujihid@nirs.go.jp
authors.forename: Hideo
authors.initials: H
authors.lastname: Tsuji
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ishii-Ohba
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Shiomi
authors.forename: Naoko
authors.initials: N
authors.lastname: Shiomi
authors.forename: Takanori
authors.initials: T
authors.lastname: Katsube
authors.forename: Masahiko
authors.initials: M
authors.lastname: Mori
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Nenoi
authors.forename: Mizuki
authors.initials: M
authors.lastname: Ohno
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yoshimura
authors.forename: Sugako
authors.initials: S
authors.lastname: Oka
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Nakabeppu
authors.forename: Kouichi
authors.initials: K
authors.lastname: Tatsumi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Muto
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Sado
mesh_terms: D000818:Animals; D024201:Bystander Effect / Q000528:radiation effects*; D063646:Carcinogenesis / Q000235:genetics / Q000528:radiation effects*; D002478:Cells, Cultured; D043171:Chromosomal Instability / Q000235:genetics / Q000528:radiation effects*; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D005260:Female; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011230:Precancerous Conditions; D011829:Radiation Dosage; D011832:Radiation Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060168:Thymocytes / Q000378:metabolism / Q000528:radiation effects; D013953:Thymus Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D017382:Reactive Oxygen Species
keywords: bystander effect; chromosomal instability; prelymphoma cell; reactive oxygen species; trisomy 15