title: Tumor Suppressor Interferon-Regulatory Factor 1 Counteracts the Germinal Center Reaction Driven by a Cancer-Associated Gammaherpesvirus.
abstract: Gammaherpesviruses are ubiquitous pathogens that are associated with the development of B cell lymphomas. Gammaherpesviruses employ multiple mechanisms to transiently stimulate a broad, polyclonal germinal center reaction, an inherently mutagenic stage of B cell differentiation that is thought to be the primary target of malignant transformation in virus-driven lymphomagenesis. We found that this gammaherpesvirus-driven germinal center expansion was exaggerated and lost its transient nature in the absence of interferon-regulatory factor 1 (IRF-1), a transcription factor with antiviral and tumor suppressor functions. Uncontrolled and persistent expansion of germinal center B cells led to pathological changes in the spleens of chronically infected IRF-1-deficient animals. Additionally, we found decreased IRF-1 expression in cases of human posttransplant lymphoproliferative disorder, a malignant condition associated with gammaherpesvirus infection. The results of our study define an unappreciated role for IRF-1 in B cell biology and provide insight into the potential mechanism of gammaherpesvirus-driven lymphomagenesis.
  
  
  OBJECTIVE
  Gammaherpesviruses establish lifelong infection in most adults and are associated with B cell lymphomas. While the infection is asymptomatic in many hosts, it is critical to identify individuals who may be at an increased risk of virus-induced cancer. Such identification is currently impossible, as the host risk factors that predispose individuals toward viral lymphomagenesis are poorly understood. The current study identifies interferon-regulatory factor 1 (IRF-1) to be one of such candidate host factors. Specifically, we found that IRF-1 enforces long-term suppression of an inherently mutagenic stage of B cell differentiation that gammaherpesviruses are thought to target for transformation. Correspondingly, in the absence of IRF-1, chronic gammaherpesvirus infection induced pathological changes in the spleens of infected animals. Further, we found decreased IRF-1 expression in human gammaherpesvirus-induced B cell malignancies.
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Wadzanai P
authors.initials: WP
authors.lastname: Mboko
authors.affiliation: Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Horatiu
authors.initials: H
authors.lastname: Olteanu
authors.affiliation: Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Avijit
authors.initials: A
authors.lastname: Ray
authors.affiliation: Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Xin
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Darrah
authors.affiliation: Division of Pediatric Pathology, Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Suresh N
authors.initials: SN
authors.lastname: Kumar
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Kulinski
authors.affiliation: Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Cui
authors.affiliation: Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Bonnie N
authors.initials: BN
authors.lastname: Dittel
authors.affiliation: Abbvie, Chicago, Illinois, USA.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gauld
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA vera@mcw.edu.
authors.forename: Vera L
authors.initials: VL
authors.lastname: Tarakanova
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000821:virology*; D002472:Cell Transformation, Viral; D018142:Gammaherpesvirinae / Q000276:immunology*; D018858:Germinal Center / Q000276:immunology* / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms; D013154:Spleen / Q000276:immunology / Q000473:pathology / Q000821:virology
chemical_list: D050856:Interferon Regulatory Factor-1