title: Enhancer mutations of Akv murine leukemia virus inhibit the induction of mature B-cell lymphomas and shift disease specificity towards the more differentiated plasma cell stage.
abstract: This study investigates the role of the proviral transcriptional enhancer for B-lymphoma induction by exogenous Akv murine leukemia virus. Infection of newborn inbred NMRI mice with Akv induced 35% plasma cell proliferations (PCPs) (consistent with plasmacytoma), 33% diffuse large B-cell lymphomas, 25% follicular B-cell lymphomas and few splenic marginal zone and small B-cell lymphomas. Deleting one copy of the 99-bp proviral enhancer sequence still allowed induction of multiple B-cell tumor types, although PCPs dominated (77%). Additional mutation of binding sites for the glucocorticoid receptor, Ets, Runx, or basic helix-loop-helix transcription factors in the proviral U3 region, however, shifted disease induction to almost exclusively PCPs, but had no major influence on tumor latency periods. Southern analysis of immunoglobulin rearrangements and ecotropic provirus integration patterns showed that many of the tumors/cell proliferations induced by each virus were polyclonal. Our results indicate that enhancer mutations weaken the ability of Akv to induce mature B-cell lymphomas prior to the plasma cell stage, whereas development of plasma cell proliferations is less dependent of viral enhancer strength.
authors.affiliation: Department of Molecular Biology, University of Aarhus, C.F. Møllers Allé, Bldg. 130, DK-8000 Aarhus C, Denmark.
authors.forename: Karina Dalsgaard
authors.initials: KD
authors.lastname: Sørensen
authors.forename: Sandra
authors.initials: S
authors.lastname: Kunder
authors.forename: Leticia
authors.initials: L
authors.lastname: Quintanilla-Martinez
authors.forename: Jonna
authors.initials: J
authors.lastname: Sørensen
authors.forename: Jörg
authors.initials: J
authors.lastname: Schmidt
authors.forename: Finn Skou
authors.initials: FS
authors.lastname: Pedersen
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D015139:Blotting, Southern; D045744:Cell Line, Tumor; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D006651:Histocytochemistry; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics; D009052:Leukemia Virus, Murine / Q000235:genetics / Q000472:pathogenicity*; D007942:Leukemia, Experimental / Q000473:pathology*; D008198:Lymph Nodes / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000473:pathology*; D051379:Mice; D008815:Mice, Inbred Strains; D008853:Microscopy; D008969:Molecular Sequence Data; D009154:Mutation; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism; D011533:Proviruses / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012192:Retroviridae Infections / Q000473:pathology*; D017384:Sequence Deletion; D013154:Spleen / Q000473:pathology; D013950:Thymus Gland / Q000473:pathology; D014412:Tumor Virus Infections / Q000473:pathology*; D016662:Virus Integration / Q000235:genetics
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D007136:Immunoglobulins; D050784:Proto-Oncogene Protein c-ets-1; D011965:Receptors, Glucocorticoid; C493726:Runx1 protein, mouse