Excessive activation?induced cytidine deaminase accumulated by proteasome inhibitors rescues abnormal class switch in...

Activation-induced cytidine deaminase (AID) is an enzyme that plays a crucial role in mediating somatic hypermutation and class-switch recombination (CSR). It has been found to be associated with aberrant immunoglobulin CSR in activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL). In the present study, MG132, a potent proteasome and calpain inhibitor, induced significant cell death in ABC-DLBCL cells and inhibited the growth of ABC-DLBCL cell xenograft tumors. The results also showed that MG132 induced AID accumulation by impairing proteasome degradation of AID. Excessive endogenous AID accumulation was observed in both AID-deficient and C57/BL6 wild-type mice treated with MG132, and apparent CSR of IgM to IgG1, IgG3 and IgE. Upon stimulation of cytokines such as LPS and/or IL-4, ABC-DLBCL cells also showed a noticeable increase in CSR of IgM to IgG1, IgG3 and IgE with decreased AID protein levels. The present study demonstrates that MG132 can induce AID accumulation, which in turn restores dysfunctional CSR in ABC-DLBCL. Using MG132 as a tool, the present study elucidates the anti-lymphoma effect of proteasome inhibitors on ABC-DLBCL by rescuing the abnormal AID-induced CSR.