Alterations in the Rho pathway contribute to Epstein-Barr virus-induced lymphomagenesis in immunosuppressed environments

Epstein-Barr virus (EBV)-positive diffuse large B cell lymphomas (EBV + -DLBLs) tend to occur in immunocompromised patients, such as the elderly or those undergoing solid organ transplantation. The pathogenesis and genomic characteristics of EBV + -DLBLs are largely unknown because of the limited availability of human samples and lack of experimental animal models. We observed the development of 25 human EBV + -DLBLs during the engraftment of gastric adenocarcinomas into immunodeficient mice. An integrated genomic analysis of the human-derived EBV + -DLBLs revealed enrichment of mutations in Rho pathway genes, including RHPN2 , and Rho pathway transcriptomic activation. Targeting the Rho pathway using a ROCK inhibitor, fasudil, markedly decreased tumor growth in EBV + -DLBL patient-derived xenograft (PDX) models. Thus, alterations in the Rho pathway appear to contribute to EBV-induced lymphomagenesis in immunosuppressed environments.