Altered histone modifications H3K4me3 and H3K27ac are associated with abnormal clonality of peripheral B-cells in cattle with bovine leukemia virus.

B-cell clonality in bovine peripheral blood changes dynamically, with progression from polyclonal to oligoclonal in persistent lymphocytosis (PL), or to monoclonal expansion in enzootic bovine leukosis (EBL). The underlying mechanisms, however, remain poorly understood. In this study, ChIP-seq analysis of histone modifications H3K4me3 and H3K27ac in peripheral blood mononuclear cells (PBMCs) was performed across polyclonal, oligoclonal, and monoclonal B-cell states. PBMCs containing a polyclonal B-cell population exhibited active histone modification features associated with immune activation and environmental responsiveness. In contrast, PBMCs containing an oligoclonal B-cell population showed enhanced metabolic activity, protein synthesis, and survival signaling, while retaining partial dependence on microenvironmental cues and chromatin plasticity, consistent with an intermediate, primed state. Furthermore, oligoclonal populations may comprise both reactive and premalignant B-cells undergoing clonal expansion. PBMCs containing a monoclonal B-cell population from EBL cases were characterized by dominant cell cycle progression, biosynthetic activity, and stress response pathways, indicative of increased proliferative autonomy and reduced microenvironmental dependence. These findings support a stepwise model of B-cell transformation, in which clonal expansion precedes overt malignancy, with progressive acquisition of autonomous growth properties.