Epstein-Barr virus (EBV) establishes a persistent latent infection in peripheral B lymphocytes in humans and is associated with a variety of malignancies and proliferative disorders. Latent membrane protein 2A (LMP2A) is one of only two viral proteins expressed in latently infected B lymphocytes in vivo. LMP2A blocks B cell receptor (BCR) signal transduction in vitro by binding the Syk and Lyn protein tyrosine kinases. To analyze the significance of LMP2A expression in vivo, transgenic mice with B cell lineage expression of LMP2A were generated. LMP2A expression results in the bypass of normal B lymphocyte developmental checkpoints allowing immunoglobulin-negative cells to colonize peripheral lymphoid organs, indicating that LMP2A possesses a constitutive signaling activity in nontransformed cells.