HDAC inhibitor chidamide synergizes with venetoclax to inhibit the growth of diffuse large B-cell lymphoma via down-regulation of MYC, BCL2, and TP53 expression  

作　　者：Cancan LUO Tiantian YU Ken H.YOUNG Li Yu 

机构地区：[1]Department of Hematology the Second Affiliated Hospital of Nanchang University,Nanchang 330006,China [2]Jiangxi ProvinceKey Laboratory of Hematology Nanchang 330006,China [3]Department of Hematopathology,Duke University School of Medicine,Duke University Medical Center,Durham,NC 27710,USA

出　　处：《Journal of Zhejiang University-Science B(Biomedicine & Biotechnology)》2022年第8期666-681,共16页浙江大学学报（英文版）B辑（生物医学与生物技术）

基　　金：supported by the National Natural Science Foundation of China(Nos.81460030 and 81770221)。

摘　　要：Diffuse large B-cell lymphoma(DLBCL) is an aggressive type of non-Hodgkin’s lymphoma. A total of 10%-15% of DLBCL cases are associated with myelocytomatosis viral oncogene homolog(MYC) and/or B-cell lymphoma-2(BCL2) translocation or amplification. BCL2 inhibitors have potent anti-tumor effects in DLBCL;however, resistance can be acquired through up-regulation of alternative anti-apoptotic proteins. The histone deacetylase(HDAC) inhibitor chidamide can induce BIM expression, leading to apoptosis of lymphoma cells with good efficacy in refractory recurrent DLBCL. In this study, the synergistic mechanism of chidamide and venetoclax in DLBCL was determined through in vitro and in vivo models. We found that combination therapy significantly reduced the protein levels of MYC, TP53, and BCL2 in activated apoptotic-related pathways in DLBCL cells by increasing BIM levels and inducing cell apoptosis. Moreover, combination therapy regulated expression of multiple transcriptomes in DLBCL cells, involving apoptosis, cell cycle, phosphorylation, and other biological processes, and significantly inhibited tumor growth in DLBCL-bearing xenograft mice. Taken together, these findings verify the in vivo therapeutic potential of chidamide and venetoclax combination therapy in DLBCL, warranting pre-clinical trials for patients with DLBCL.

关 键 词：Diffuse large B-cell lymphoma(DLBCL) Histone deacetylase(HDAC)inhibitor Venetoclax MYC BCL2 TP53 

分 类 号：R733.1[医药卫生—肿瘤]