Tumor Suppressor Interferon-Regulatory Factor 1 Counteracts the Germinal Center Reaction Driven by a Cancer-Associated Gammaherpesvirus.

Authors:
Wadzanai P Mboko
Wadzanai P Mboko
Medical College of Wisconsin
United States
Horatiu Olteanu
Horatiu Olteanu
Medical College of Wisconsin
United States
Avijit Ray, PhD
Avijit Ray, PhD
AbbVie
Senior Scientist II
Immunology, Immuno-oncology, Autoimmunity and Inflammation, Immune tolerance
North Chicago, IL | United States
Gang Xin
Gang Xin
Shantou University Medical College
China
Eric J Darrah
Eric J Darrah
Microbiology and Molecular Genetics
Suresh N Kumar
Suresh N Kumar
Medical College of Wisconsin
Joseph M Kulinski
Joseph M Kulinski
Microbiology and Molecular Genetics
Weiguo Cui
Weiguo Cui
Yale University School of Medicine
United States

J Virol 2015 Dec 30;90(6):2818-29. Epub 2015 Dec 30.

Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

Unlabelled: 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.

Importance: 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.

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Source
http://dx.doi.org/10.1128/JVI.02774-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4810652PMC

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December 2015
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