Peripheral B cells from HCV-associated B cell non-Hodgkin’s lymphoma patients display clonal expansion and an anergic-like transcriptional profile

Authors

• AN Henningm HJ Alter
• N Dashorj
• V De Giorgi

Abstract

Chronic hepatitis C virus (HCV) infection remains a global health issue, with its role in B cell lymphoproliferative disorders, including B cell non-Hodgkin’s lymphoma (BNHL), of increasing concern. Epidemiological and clinical evidence strongly support a causal role of chronic HCV infection in BNHL pathogenesis; however, the molecular mechanisms underlying this association are poorly understood. To help elucidate this relationship, we performed RNA-sequencing on peripheral B cells collected from chronic HCV-infected patients with or without BNHL, as well as BNHL-only patients and healthy controls. In peripheral B cells from HCV-associated BNHL patients, we observed enrichment of a transcriptional signature associated with B cell anergy. This included overexpression of inhibitory receptors, pro-apoptotic genes, and BCR signaling inhibitors, as well as enrichment of anergic-like gene sets. BCR repertoire analysis of our RNA-seq data identified significant clonal expansion in peripheral B cells from HCV-associated BNHL patients, and we identified 7 expanded clonotypes corresponding to 6 Ig variable gene loci. Expanded clones included Ig genes whose encoded BCRs have been associated with viral- and non-viral-related lymphoma, autoimmunity, and autoreactivity. We also observed strong positive correlation between differentially expressed epigenetic regulatory genes and degree of clonal expansion, suggesting epigenetic regulation may be involved in B cell anergy. Studies are underway to further interrogate peripheral clonal expansion via BCR-sequencing and to investigate the BCR repertoire and transcriptome in matched lymphoma tissues. We believe these results have implications for HCV-associated BNHL treatment and monitoring and suggest dysregulation of the anergic state may play a role in HCV-associated lymphoprogression.

Scientific Focus Area: Cancer Biology

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