Peripheral B cells from patients with HCV-associated B cell lymphoma exhibit an anergic-like transcriptional profile and evidence of clonal expansion

Chronic HCV infection remains a global health concern due to its involvement in hepatic and extrahepatic diseases, including B cell non-Hodgkin's lymphoma (BNHL). Clinical and epidemiological evidence support a causal role for HCV in BNHL development, although mechanistic insight is lacking. We performed RNA-sequencing on peripheral B cells from patients with HCV, BNHL, and HCV-associated BNHL to identify unique and shared transcriptional profiles associated with transformation. In patients with HCV-associated BNHL, we observed enrichment of an anergic gene signature and evidence of clonal expansion that was correlated with expression of epigenetic regulatory genes. Our data support a role for viral-mediated clonal expansion of anergic-like B cells in HCV-associated BNHL development, and suggest epigenetic dysregulation as a potential mechanism driving expansion. We propose epigenetic mechanisms may be involved in both HCV-associated lymphoma and regulation of B cell anergy, representing an attractive target for clinical interventions. Overall design: mRNA profiling of peripheral B cells isolated from patients with chronic HCV infection (n=9), B cell non-Hodgkin's lymphoma (n=6), HCV-associated B cell non-Hodgkin's lymphoma (n=6), and healthy donors (n=6)