An Beiying, Zhu Shan, Li Tete, Wu Jing, Zang Guoxia, Lv Xinping, Qiao Yuan, Huang Jing, Shao Yan, Cui Jiuwei, Liu Yong-Jun, Chen Jingtao
Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China.
Department of Clinical Laboratory, The First Hospital of Jilin University, Changchun, China.
Front Cell Dev Biol. 2020 Apr 22;8:262. doi: 10.3389/fcell.2020.00262. eCollection 2020.
Diffuse large B cell lymphoma (DLBCL) is associated with aggressive clinical cases and poor prognosis despite recent advances in disease treatment. In activated B-cell-like (ABC)-DLBCL, the most severe damaged signaling pathways converge to aberrantly activate the Toll-like receptor (TLR) 7/9/MyD88 pathways, leading to the avoidance of cell death and resistance to chemotherapy. A gain of function mutation in MyD88 (MyD88 L265P) enhanced the NF-κB and JAK-STAT signaling pathways and was associated with dysregulation of TLR signaling in the pathogenesis of ABC-DLBCL. Therefore, inhibition of the TLR signaling network may improve clinical outcomes. In this study, we designed a synthesized oligodeoxynucleotide-based antagonist of TLR7 and TLR9, referred to as HJ901, which competitively binds to TLR7/9. We profiled HJ901 inhibition in various DLBCL cell lines and verified tumor suppression in a xenograft mouse model. We found that HJ901 treatment significantly reduced TLR7- and TLR9-mediated cell proliferation and cytokine production in a time- and dose-dependent manner in various DLBCL cell lines expressing the MyD88 L265P mutation. Moreover, HJ901 prevented tumor growth and downregulated the NF-κB and JAK2-STAT3 signaling pathways in a DLBCL xenograft mouse model with the MyD88 L265P mutation. These results reveal that the anti-tumor effects of the synthesized oligodeoxynucleotide-based antagonist, HJ901, which competitively binds to TLR7/9, may be associated with the downregulation of the NF-κB and JAK2-STAT3 signaling pathways and provide rationale for treating ABC-DLBCL patients with the MyD88 L265P mutation.
弥漫性大B细胞淋巴瘤（DLBCL）尽管在疾病治疗方面取得了最新进展，但仍与侵袭性临床病例和不良预后相关。在活化B细胞样（ABC）-DLBCL中，受损最严重的信号通路会异常激活Toll样受体（TLR）7/9/MyD88通路，从而导致细胞死亡规避和化疗耐药。MyD88（MyD88 L265P）的功能获得性突变增强了NF-κB和JAK-STAT信号通路，并与ABC-DLBCL发病机制中TLR信号的失调有关。因此，抑制TLR信号网络可能改善临床结果。在本研究中，我们设计了一种基于合成寡脱氧核苷酸的TLR7和TLR9拮抗剂，称为HJ901，它能竞争性结合TLR7/9。我们分析了HJ901在各种DLBCL细胞系中的抑制作用，并在异种移植小鼠模型中验证了其肿瘤抑制作用。我们发现，在表达MyD88 L265P突变的各种DLBCL细胞系中，HJ901处理以时间和剂量依赖性方式显著降低了TLR7和TLR9介导的细胞增殖和细胞因子产生。此外，在具有MyD88 L265P突变的DLBCL异种移植小鼠模型中，HJ901可阻止肿瘤生长并下调NF-κB和JAK2-STAT3信号通路。这些结果表明，竞争性结合TLR7/9的基于合成寡脱氧核苷酸的拮抗剂HJ901的抗肿瘤作用可能与NF-κB和JAK2-STAT3信号通路的下调有关，并为治疗具有MyD88 L265P突变的ABC-DLBCL患者提供了理论依据。
