Tumor suppressor interferon-regulatory factor 1 counteracts the germinal center reaction driven by a cancer-associated gammaherpesvirus

WP Mboko, H Olteanu, A Ray, G Xin, EJ Darrah… - Journal of …, 2016 - Am Soc Microbiol
WP Mboko, H Olteanu, A Ray, G Xin, EJ Darrah, SN Kumar, JM Kulinski, W Cui, BN Dittel…
Journal of virology, 2016Am Soc Microbiol
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 …
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.
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.
American Society for Microbiology