Friday, May 9, 2025
5/9/2025
Defining the function of EWSR1 in restricting germinal center B cell responses and lymphoma - Project Summary Oncogenic viruses, such as the gammaherpesviruses, Epstein-Barr Virus (EBV) and Kaposi’s sarcoma- associated herpesvirus (KSHV), are thought to contribute to 12-20% of human cancers worldwide. EBV and KSHV are highly prevalent viruses responsible for a wide variety of malignancies including several types of B cell lymphomas. Due to their strict species specificity, the key in vivo mechanisms that these viruses use to establish infection and cause disease have been difficult to define. Murine gammaherpesvirus 68 (MHV68) is genetically and pathogenically related to both EBV and KSHV and provides a robust model to study in vivo aspects of gammaherpesvirus pathogenesis and disease. Memory B cells and plasma cells are essential components of the adaptive immune response that are critical for defending the host from an array of foreign pathogens. These cells are generated in lymphoid structures called germinal centers (GC) that form in response to naïve B cells encountering their specific antigen. GC responses involve numerous dynamic processes, including proliferation, survival selection, DNA damage, and hypermutation. These processes are essential to generate refined antigen-specific B cells but are also fraught with danger due to their potential to result in dangerous outcomes such as B cell malignancies and autoimmune disease. Thus, GC reactions must be tightly regulated by the host. Gammaherpesviruses are thought to manipulate GC B cell biology by infecting naïve B cells and driving those cells through GC reactions, independent of antigen, to establish lifelong latent infection in the memory B cells reservoir. Thus, host immune responses and gammaherpesvirus biology are deeply intertwined in the GC B cell compartment. Work described in this proposal been developed from previous data from my lab demonstrating that the MHV68 miRNA mghv-miRNA-7-5p specifically represses the host transcript EWSR1 to promote latent infection of GC B cells. EWSR1 is a multifunctional protein that is well-known for its role as a fusion protein in Ewing’s sarcoma, but for which a role in mature B cell biology or gammaherpesvirus biology had never been described. We have now demonstrated that, in vivo, during both virus infection of GC B cells and nonviral antigen-stimulated immune responses, EWSR1 functions a negative regulator to constrain the magnitude of GC B cell responses. However, the specific function that EWSR1 carries out in GC reactions is unknown. We hypothesize that EWSR1 acts to constrain GC B cell reactions through regulation of the critical transcription factor BCL6, promoting exit of B cells from the GC, and thereby preventing deleterious outcomes. To test this hypothesis, I will: (Aim 1) determine how repression of EWSR1 expands germinal center processes, (Aim 2) test the hypothesis that EWSR1 regulates post-translational modification and subsequent degradation of BCL6 to regulate GC B cell entry and recycling, and (Aim 3) determine whether repression of EWSR1 is required for MHV68 lymphomagenesis.
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