Stage‐Dependent Transcriptional Reprogramming of B‐Cell Receptor Signaling and Antigen Presentation During Bovine Leukemia Virus–Driven Lymphomagenesis

Bovine leukemia virus (BLV), an oncogenic deltaretrovirus, establishes lifelong infection in cattle and induces enzootic bovine leukosis in a subset of animals following prolonged latency. Despite extensive evidence of immune dysregulation, stage-specific transcriptional reprogramming of B cells, the primary viral reservoir remains incompletely understood. In this study, we performed a targeted RNA-sequencing analysis to characterize B-cell-associated transcriptional profiles across three clinical stages: uninfected controls (CT), asymptomatic BLV-infected cattle (AC), and persistent lymphocytosis (PL). Differential gene expression analysis revealed a dynamic, stage-dependent remodeling of B-cell immune functions. Asymptomatic infection was characterized by significant upregulation of key B-cell receptor (BCR) signaling components, including CD79B and SYK, alongside increased expression of major histocompatibility complex class II genes (BoLA-DRA, BoLA-DRB3) and immunoglobulin assembly gene JCHAIN, indicating enhanced antigen responsiveness and partial activation of antibody-related pathways. However, transcriptional regulators of terminal plasma cell differentiation (PRDM1 and XBP1) remained unchanged, suggesting incomplete maturation. In contrast, progression to persistent lymphocytosis was associated with attenuation of canonical BCR signaling and reduced expression of antigen presentation and immunoglobulin assembly genes relative to the asymptomatic stage. Notably, germinal center-associated transcription factors (BCL6, AICDA, RGS13, MEF2B) remained largely unchanged across all comparisons, indicating that BLV-driven lymphomagenesis does not resemble a classical germinal center-derived process. Collectively, these findings support a biphasic model of BLV-induced B-cell modulation, characterized by early immune activation followed by functional reprogramming and immune attenuation during disease progression. This stage-dependent remodeling provides new mechanistic insights into BLV pathogenesis and B-cell transformation.