Impact of proviral integration of bovine leukemia virus near oncogenes on the early onset of lymphoma in cattle under 3 years of age

Bovine leukemia virus (BLV) causes enzootic bovine leukosis (EBL), resulting in serious economic losses. Early-onset EBL in cattle under 3 years of age compromises the profit-generating potential of cattle, resulting in substantial economic losses. However, pathogenic mechanisms underlying early-onset EBL remain unclear. We identified 19 integration sites (ISs) from eight cattle with lymphoma under 3 years of age and compared them with 187 ISs from 79 cattle with lymphoma over 3 years of age. The distribution of ISs within repetitive regions, CpG islands, exons, introns, and intergenic regions did not differ between cattle with lymphoma under 3 years of age and those over 3 years of age. Among 20 IS-related genes detected in eight cattle with lymphoma under 3 years of age, five (25%) were oncogenes. This proportion was significantly higher than that in cattle aged over 3 years (6.2%). However, cattle with lymphoma under and over 3 years did not differ in frequency of integration into the "common EBL-related cluster" previously identified through protein-protein interactions analysis of BLV ISs in a large cohort. Thus, rather than integration into the "common EBL-related cluster" associated with the onset of EBL, integration near oncogenes contributing directly to oncogenesis could be one of the factors for early-onset EBL. This study provides new insights into the association between BLV IS and early-onset EBL.