Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing 400037, China.
State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing 400037, China.
Chin Med J (Engl). 2023 Jun 20;136(12):1448-1458. doi: 10.1097/CM9.0000000000002686. Epub 2023 Apr 28.
Exploring the underlying mechanism of rituximab resistance is critical to improve the outcomes of patients with diffuse large B-cell lymphoma (DLBCL). Here, we tried to identify the effects of the axon guidance factor semaphorin-3F (SEMA3F) on rituximab resistance as well as its therapeutic value in DLBCL.
The effects of SEMA3F on the treatment response to rituximab were investigated by gain- or loss-of-function experiments. The role of the Hippo pathway in SEMA3F-mediated activity was explored. A xenograft mouse model generated by SEMA3F knockdown in cells was used to evaluate rituximab sensitivity and combined therapeutic effects. The prognostic value of SEMA3F and TAZ (WW domain-containing transcription regulator protein 1) was examined in the Gene Expression Omnibus (GEO) database and human DLBCL specimens.
We found that loss of SEMA3F was related to a poor prognosis in patients who received rituximab-based immunochemotherapy instead of chemotherapy regimen. Knockdown of SEMA3F significantly repressed the expression of CD20 and reduced the proapoptotic activity and complement-dependent cytotoxicity (CDC) activity induced by rituximab. We further demonstrated that the Hippo pathway was involved in the SEMA3F-mediated regulation of CD20. Knockdown of SEMA3F expression induced the nuclear accumulation of TAZ and inhibited CD20 transcriptional levels via direct binding of the transcription factor TEAD2 and the CD20 promoter. Moreover, in patients with DLBCL, SEMA3F expression was negatively correlated with TAZ, and patients with SEMA3F low TAZ high had a limited benefit from a rituximab-based strategy. Specifically, treatment of DLBCL cells with rituximab and a YAP/TAZ inhibitor showed promising therapeutic effects in vitro and in vivo .
Our study thus defined a previously unknown mechanism of SEMA3F-mediated rituximab resistance through TAZ activation in DLBCL and identified potential therapeutic targets in patients.
探索利妥昔单抗耐药的潜在机制对于改善弥漫性大 B 细胞淋巴瘤（DLBCL）患者的预后至关重要。在这里，我们试图确定轴突导向因子 SEMA3F（信号素 3F）对利妥昔单抗耐药的影响及其在 DLBCL 中的治疗价值。
通过增益或失活实验研究 SEMA3F 对利妥昔单抗治疗反应的影响。探索 Hippo 通路在 SEMA3F 介导的活性中的作用。使用通过 SEMA3F 敲低在细胞中生成的异种移植小鼠模型来评估利妥昔单抗敏感性和联合治疗效果。在基因表达综合数据库（GEO）和人类 DLBCL 标本中检查 SEMA3F 和 TAZ（WW 结构域包含转录调节剂蛋白 1）的预后价值。
我们发现，与接受基于利妥昔单抗的免疫化疗而不是化疗方案的患者相比，SEMA3F 的缺失与预后不良有关。SEMA3F 的敲低显著抑制了 CD20 的表达，并降低了利妥昔单抗诱导的促凋亡活性和补体依赖性细胞毒性（CDC）活性。我们进一步证明 Hippo 通路参与了 SEMA3F 介导的 CD20 调节。SEMA3F 表达的敲低诱导 TAZ 的核积累，并通过转录因子 TEAD2 和 CD20 启动子的直接结合抑制 CD20 转录水平。此外，在 DLBCL 患者中，SEMA3F 表达与 TAZ 呈负相关，并且 SEMA3F 低 TAZ 高的患者从基于利妥昔单抗的策略中获益有限。具体而言，利妥昔单抗和 YAP/TAZ 抑制剂联合治疗 DLBCL 细胞在体外和体内均显示出有希望的治疗效果。
因此，我们通过 DLBCL 中 TAZ 的激活定义了 SEMA3F 介导的利妥昔单抗耐药的一个以前未知的机制，并确定了患者中的潜在治疗靶点。
