Abstract
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.
摘要
目的
探讨表观遗传学组蛋白去乙酰化酶(HDAC)抑制剂西达本胺与BCL2抑制剂维奈托克的联合对弥漫性大B细胞淋巴瘤(DLBCL)生长的影响及相关机制。
创新点
本研究首次探索了将西达本胺和维奈托克联合作用于MYC+/BCL2+DLBCL, 使用二代测序(NGS)开创性地从表观遗传学和基因蛋白层面探讨这种联合用药的效果及作用机制。
方法
利用生物信息学技术分析表观遗传学HDAC基因与BCL2基因之间的相关性; 体外应用DHL细胞株DB(MYC/BCL2重排)和DEL细胞株SUDHL-4(MYC、BCL2表达)分别进行单药和联合用药处理, 通过CCK-8法检测细胞活力, 流式细胞术检测细胞凋亡和周期, RNA测序和蛋白质印迹(western blot)检测MYC、BCL2、TP53等相关基因的mRNA水平及蛋白的表达; 体内建立DLBCL异种移植小鼠模型进行单药和联合用药治疗, 分析并评价药物治疗后皮下瘤的大小和病理切片。
结论
西达本胺与维奈托克协同抑制DLBCL的生长, 通过调控表观遗传的改变, 沉默MYC、TP53的表达, 降低抗凋亡蛋白BCL2表达以及增加促凋亡蛋白BIM表达, 诱导肿瘤细胞的凋亡和细胞周期阻滞。
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Acknowledgments
This work was supported by the National Natural Science Foundation of China (Nos. 81460030 and 81770221).
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Cancan LUO performed research design, the experimental research, and data analysis, wrote and edited the manuscript. Tiantian YU performed the experimental research and data analysis. Ken H. YOUNG performed the research design and data analysist. Li YU performed research design and data analysis, wrote and edited the manuscript. All authors have read and approved the final manuscript, and therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data.
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Cancan LUO, Tiantian YU, Ken H. YOUNG, and Li YU declare that they have no conflict of interest.
This study was carried out in accordance with the recommendations of the Ethics Committee of the Second Affiliated Hospital of Nanchang University. The protocol was approved by the Ethics Committee of the Second Affiliated Hospital of Nanchang University. All subjects gave written informed consent in accordance with the Declaration of Helsinki.
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Luo, C., Yu, T., Young, K.H. et al. 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. J. Zhejiang Univ. Sci. B 23, 666–681 (2022). https://doi.org/10.1631/jzus.B2200016
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DOI: https://doi.org/10.1631/jzus.B2200016