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Excessive AID accumulated by proteasome inhibitors rescues abnormal class switch in ABC-DLBCL
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  • Zhuangwei Lv,
  • Chen Xu,
  • Zhenzhen Wang,
  • Zixian Liu,
  • Junna Jiao
Zhuangwei Lv
Xinxiang Medical University
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Chen Xu
The Affiliated Hospital of Qingdao University
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Zhenzhen Wang
Xinxiang Medical University
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Zixian Liu
Xinxiang Medical University
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Junna Jiao
Xinxiang Medical University

Corresponding Author:[email protected]

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Abstract

Activation-induced cytidine deaminase (AID) is an enzyme that plays a crucial role in mediating somatic hypermutation (SHM) and class-switch recombination (CSR). It has been found to be related to aberrant immunoglobulin CSR in activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL). In a previous study, we demonstrated that proteasome inhibitor MG132 had a significant anti-lymphoma effect on ABC-DLBCL, but the mechanism behind this remains unknown. In this study, we observed that MG132 induced significant cell death in ABC-DLBCL cells and inhibited the growth of ABC-DLBCL cell xenograft tumors. Our results also showed that MG132 impairs proteasome degradation of AID, leading to AID accumulation. Using AID-deficient C57/BL6 mice as a control, we found excessive endogenous AID accumulation in C57/BL6 wildtype mice treated with MG132, and apparent CSR of IgM to IgG1, IgG3 and IgE. In stimulation of cytokines such as LPS and/or IL4, ABC-DLBCL cells showed a noticeable increase in CSR of IgM to IgG1, IgG3 and IgE with decreased AID ubiquitination. This study demonstrates that MG132 can induce AID accumulation, which in turn restores dysfunctional CSR in ABC-DLBCL. The use of MG132 as a tool elucidates the anti-lymphoma effect of proteasome inhibitors on ABC-DLBCL by rescuing the abnormal AID-induced CSR.