title: Monoclonal B-cell hyperplasia and leukocyte imbalance precede development of B-cell malignancies in uracil-DNA glycosylase deficient mice.
abstract: Ung-deficient mice have reduced class switch recombination, skewed somatic hypermutation, lymphatic hyperplasia and a 22-fold increased risk of developing B-cell lymphomas. We find that lymphomas are of follicular (FL) and diffuse large B-cell type (DLBCL). All FLs and 75% of the DLBCLs were monoclonal while 25% were biclonal. Monoclonality was also observed in hyperplasia, and could represent an early stage of lymphoma development. Lymphoid hyperplasia occurs very early in otherwise healthy Ung-deficient mice, observed as a significant increase of splenic B-cells. Furthermore, loss of Ung also causes a significant reduction of T-helper cells, and 50% of the young Ung(-/-) mice investigated have no detectable NK/NKT-cell population in their spleen. The immunological imbalance is confirmed in experiments with spleen cells where the production of the cytokines interferon gamma, interleukin 6 and interleukin 2 is clearly different in wild type and in Ung-deficient mice. This suggests that Ung-proteins, directly or indirectly, have important functions in the immune system, not only in the process of antibody maturation, but also for production and functions of immunologically important cell types. The immunological imbalances shown here in the Ung-deficient mice may be central in the development of lymphomas in a background of generalised lymphoid hyperplasia.
authors.affiliation: Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim.
authors.forename: Sonja
authors.initials: S
authors.lastname: Andersen
authors.forename: Madelene
authors.initials: M
authors.lastname: Ericsson
authors.forename: Hong Yan
authors.initials: HY
authors.lastname: Dai
authors.forename: Javier
authors.initials: J
authors.lastname: Peña-Diaz
authors.forename: Geir
authors.initials: G
authors.lastname: Slupphaug
authors.forename: Hilde
authors.initials: H
authors.lastname: Nilsen
authors.forename: Harald
authors.initials: H
authors.lastname: Aarset
authors.forename: Hans E
authors.initials: HE
authors.lastname: Krokan
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology*; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D004247:DNA / Q000235:genetics; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005838:Genotype; D006965:Hyperplasia / Q000473:pathology*; D037102:Lectins / Q000494:pharmacology; D007962:Leukocytes / Q000473:pathology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D016393:Lymphoma, B-Cell / Q000175:diagnosis / Q000473:pathology*; D051379:Mice; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D013601:T-Lymphocytes / Q000473:pathology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D051981:Uracil-DNA Glycosidase / Q000172:deficiency* / Q000235:genetics
chemical_list: D016207:Cytokines; D037102:Lectins; D008070:Lipopolysaccharides; D003208:Concanavalin A; D004247:DNA; D051981:Uracil-DNA Glycosidase; D013755:Tetradecanoylphorbol Acetate