Arsenic trioxide inhibits refractory lymphoma by targeting BCL6 and triggering degradation

Summary: Abstract Body: Arsenic trioxide (As2O3, ATO), one of the first-line anticancer drugs in clinical practice, is characterized by multi-target properties and involved in varieties of biological responses. BCL6 (B-cell lymphoma 6 protein), a transcriptional repressor and proto-oncogene, is a potential target for refractory lymphoma and IVLBCL with a typical cutaneous phenotype. It is reported that ATO downregulate the expression level of BCL6 and inhibit lymphoma. However, the mechanism is not clear. In this study, we demonstrated the effectiveness of ATO in inhibiting the proliferation of lymphoma cell lines and identified arsenic-binding proteins in two lymphoma cell lines by proteomics, in which BCL6 was identified as a key target protein. In addition, we confirmed that AsIII directly bind to the zinc finger domain of BCL6. We further verified that ATO exerts its therapeutic effect by promoting BCL6 ubiquitination to induce its proteasomal degradation. In addition, the effectiveness of ATO for the treatment of lymphoma in vivo has proved through animal models. This work reveals the mode of action of the ATO in molecular level and its specificity for refractory lymphoma, and is expected to be a potential therapeutical strategy for refractory lymphoma and IVLBCL with a typical skin phenotype. Xuqiao Hu¹, Derong Chen¹, Wenxu Hong¹ 1. Shenzhen Center of Chronic Disease Control, Shenzhen Insititute of Dermatology, Shenzhen, China. Translational Studies: Cell and Molecular Biology