title: EBI2 overexpression in mice leads to B1 B-cell expansion and chronic lymphocytic leukemia-like B-cell malignancies.
abstract: Human and mouse chronic lymphocytic leukemia (CLL) develops from CD5+B cells that in mice and macaques are known to define the distinct B1a B-cell lineage. B1a cells are characterized by lack of germinal center (GC) development, and the B1a cell population is increased in mice with reduced GC formation. As a major mediator of follicular B-cell migration, the G protein-coupled receptor Epstein-Barr virus-induced gene 2 (EBI2orGPR183) directs B-cell migration in the lymphoid follicles in response to its endogenous ligands, oxysterols. Thus, upregulation of EBI2 drives the B cells toward the extrafollicular area, whereas downregulation is essential for GC formation. We therefore speculated whether increased expression of EBI2 would lead to an expanded B1 cell subset and, ultimately, progression to CLL. Here, we demonstrate that B-cell-targeted expression of human EBI2 (hEBI2) in mice reduces GC-dependent immune responses, reduces total immunoglobulin M (IgM) and IgG levels, and leads to increased proliferation and upregulation of cellular oncogenes. Furthermore, hEBI2 overexpression leads to an abnormally expanded CD5+B1a B-cell subset (present as early as 4 days after birth), late-onset lymphoid cancer development, and premature death. These findings are highly similar to those observed in CLL patients and identify EBI2 as a promoter of B-cell malignancies.
authors.affiliation: Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kristine
authors.initials: K
authors.lastname: Niss Arfelt
authors.affiliation: Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Line
authors.initials: L
authors.lastname: Barington
authors.affiliation: Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Tau
authors.initials: T
authors.lastname: Benned-Jensen
authors.affiliation: Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Valentina
authors.initials: V
authors.lastname: Kubale
authors.affiliation: Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD; and.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Kovalchuk
authors.affiliation: Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Viktorija
authors.initials: V
authors.lastname: Daugvilaite
authors.affiliation: Department of Immunology and Microbiology and.
authors.forename: Jan Pravsgaard
authors.initials: JP
authors.lastname: Christensen
authors.affiliation: Department of Immunology and Microbiology and.
authors.forename: Allan Randrup
authors.initials: AR
authors.lastname: Thomsen
authors.affiliation: Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kristoffer L
authors.initials: KL
authors.lastname: Egerod
authors.affiliation: Department of Immunology and Microbiology and.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Bassi
authors.affiliation: Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Katja
authors.initials: K
authors.lastname: Spiess
authors.affiliation: Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Thue W
authors.initials: TW
authors.lastname: Schwartz
authors.affiliation: Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD; and.
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Wang
authors.affiliation: Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD; and.
authors.forename: Herbert C
authors.initials: HC
authors.lastname: Morse
authors.affiliation: Department of Immunology and Microbiology and.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Holst
authors.affiliation: Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mette M
authors.initials: MM
authors.lastname: Rosenkilde
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology*; D018956:CD5 Antigens / Q000032:analysis / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic; D018858:Germinal Center / Q000166:cytology / Q000276:immunology / Q000473:pathology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008223:Lymphoma / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D051379:Mice; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000276:immunology; D015854:Up-Regulation
chemical_list: D018956:CD5 Antigens; C080105:GPR183 protein, human; D043562:Receptors, G-Protein-Coupled