Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.
Dis Markers. 2022 Jun 21;2022:3276925. doi: 10.1155/2022/3276925. eCollection 2022.
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous malignant lymphoma with distinct characteristics. Patients with treatment failure after the standard immunochemotherapy have worse prognosis, which implies the necessity to uncover novel targets. The C-X-C chemokine receptor 4 (CXCR4) overexpression has been identified in several hematopoietic malignancies. However, the expression signatures and prognostic significance of CXCR4 in DLBCL associated with clinicopathological features remain unclear.
Gene expression profiles of DLBCL were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Then, a meta-analysis with an integrated bioinformatic analysis was performed to assess the relationship between CXCR4 expression and clinicopathological features of DLBCL. Finally, experimental verification including immunohistochemical (IHC) staining and real-time quantitative PCR (qPCR) was carried out using patient samples. In vitro cell line viability tests were conducted using CXCR4 inhibitor WZ811.
DLBCL patients with activated B-cell-like (ABC) subtype have higher expression level of CXCR4 with worse survival. Differential expressed genes in the CXCR4-upregulation group were enriched in canonical pathways associated with oncogenesis. DLBCL with CXCR4 upregulation had lower degree of CD8 T cell infiltration. TIMER analysis demonstrated that the CXCR4 expression was positively correlated with the expression of CD5, MYC, NOTCH1, PDCD1, CD274, mTOR, FOXO1, and hnRNPA2B1 in DLBCL. IHC study in patient samples showed the positive correlation between CXCR4 and nongerminal center B-cell (non-GCB) subtype and mTOR expression. Meanwhile, quantitative polymerase chain reaction results revealed that high CXCR4 mRNA level was correlated to double-hit DLBCL. Finally, cell viability test showed that WZ811 exerted antiproliferation effect in DLBCL cell lines in a dose-dependent manner.
CXCR4 was upregulated in ABC-DLBCL associated with worse prognosis. Our analysis predicted CXCR4 as a potential target for DLBCL treatment, which may serve as an inhibitor both on BCR signaling and nuclear export warranting further investigation in clinical trials.
弥漫性大 B 细胞淋巴瘤（DLBCL）是一种具有明显特征的异质性恶性淋巴瘤。标准免疫化学疗法治疗失败的患者预后更差，这意味着需要揭示新的靶点。已经在几种血液恶性肿瘤中鉴定出 C-X-C 趋化因子受体 4（CXCR4）过表达。然而，与临床病理特征相关的 CXCR4 在 DLBCL 中的表达特征和预后意义尚不清楚。
从癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）获得 DLBCL 的基因表达谱。然后，进行荟萃分析和综合生物信息学分析，以评估 CXCR4 表达与 DLBCL 临床病理特征的关系。最后，使用患者样本进行包括免疫组织化学（IHC）染色和实时定量 PCR（qPCR）在内的实验验证。使用 CXCR4 抑制剂 WZ811 进行体外细胞系活力测试。
具有激活 B 细胞样（ABC）亚型的 DLBCL 患者具有更高的 CXCR4 表达水平和更差的生存。CXCR4 上调组差异表达基因富集在与肿瘤发生相关的经典途径中。CXCR4 上调的 DLBCL 具有较低程度的 CD8 T 细胞浸润。TIMER 分析表明，CXCR4 表达与 DLBCL 中 CD5、MYC、NOTCH1、PDCD1、CD274、mTOR、FOXO1 和 hnRNPA2B1 的表达呈正相关。患者样本的免疫组织化学研究表明，CXCR4 与非生发中心 B 细胞（non-GCB）亚型和 mTOR 表达呈正相关。同时，定量聚合酶链反应结果表明，高 CXCR4 mRNA 水平与双打击 DLBCL 相关。最后，细胞活力测试表明，WZ811 以剂量依赖性方式在 DLBCL 细胞系中发挥抗增殖作用。
ABC-DLBCL 中 CXCR4 上调与预后更差相关。我们的分析预测 CXCR4 是 DLBCL 治疗的潜在靶点，它可能作为 BCR 信号和核输出的抑制剂，值得在临床试验中进一步研究。
