Syk, a novel therapeutic target for PTLD, drives Epstein Barr Virus B cell lymphoma growth and survival through the PI3K/Akt pathway (141.23)

Abstract

Abstract Post-transplant lymphoproliferative disorder (PTLD)-associated Epstein Barr Virus (EBV)+ B cell lymphomas are a serious, and often fatal, complication of solid organ and bone marrow transplantation. In EBV+ PTLD, latent membrane protein 2a (LMP2a), a mimic of the B cell receptor, provides a constitutive survival signal to latently infected cells. This signal is transmitted through the sequestering and activation of Lyn and Syk and subsequent activation of downstream survival pathways. We hypothesized that inhibition of Syk activity would diminish growth of EBV+ B cell lymphoma lines derived from patients with PTLD. Treatment with R406, a novel Syk inhibitor, decreased proliferation and induced apoptosis of PTLD lines. While the NFkB and p38 pathways were unaffected after PTLD lines were treated with R406, both the Akt and Erk pathways were inhibited. Akt is constitutively active in these cells, and treatment with R406 led to decreased Akt-dependent autocrine IL-10 secretion. These data indicate that Syk mediates its effects on EBV+ PTLD growth and survival through activation of the PI3K/Akt pathway. Syk inhibitors, such as R406, may serve as an effective therapeutic strategy for EBV+ PTLD.