B cell receptor signaling promotes endogenous retrovirus-associated lymphomagenesis in T-cell-deficient B6-Ly5.1 mice.

Endogenous retroviruses (ERVs) are typically epigenetically silenced but can contribute to tumorigenesis upon reactivation under immunodeficient conditions. However, the precise physiological triggers and microenvironmental mechanisms driving ERV-mediated oncogenesis in vivo remain poorly understood. Here, we demonstrate that B cell receptor (BCR) signaling triggers ERV (specifically Emv10) reactivation and promotes lymphomagenesis in T cell-deficient B6-Ly5.1 mice. The resulting tumors exhibited a distinct germinal center B cell-like (GCL) phenotype with somatic hypermutations and harbored recurrent eMLV proviral insertions near the Plch2 locus on chromosome 4, associated with aberrant activation of Plch2. In vivo, chronic antigen stimulation with NP-Ficoll significantly accelerated lethal GCL development, accompanied by systemic accumulation of malignant cells. Crucially, in a model where direct BCR stimulation was restricted to a minor subset of λ+ B cells, the accelerated malignancies arose predominantly from non-stimulated λ- B cell clones. These findings suggest that physiological BCR activation may promote lymphomagenesis through a non-cell-autonomous mechanism. Our model highlights a novel, vital role for T cell-mediated immune surveillance in restricting ERV-driven tumor propagation across the host B cell compartment.