Tin Waihin, Xiao Cuilan, Sun Kexin, Zhao Yijun, Xie Mengyun, Zheng Jiayin, Wang Ying, Liu Sixi, Yu Uet
Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Department of Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China.
Front Oncol. 2024 Aug 19;14:1427776. doi: 10.3389/fonc.2024.1427776. eCollection 2024.
Neutrophil extracellular traps (NETs) can be attributed to the metastasis, occurrence, and immune evasion of cancer cells. We investigated the prognostic value of NET-related genes in childhood acute lymphoblastic leukemia (cALL) patients.
Differential gene expression analysis was conducted on samples collected from public databases. Grouping them based on the expression level of NET-related genes, we assessed the correlation between immune cell types and the risk score for having a poor prognosis of cALL, with an evaluation of the sensitivity of drugs used in cALL. We further divided the groups, integrating survival data. Subsequently, methods including multivariable Cox algorithms, least absolute shrinkage and selection operator (LASSO), and univariable were utilized to create a risk model predicting prognosis. Experiments in cell lines and animals were performed to explore the functions of TRIM8, a gene selected by the model. To validate the role of TRIM8 in leukemia development, lentivirus-mediated overexpression or knockdown of TRIM8 was employed in mice with T-ALL and B-ALL.
Kaplan-Meier (KM) analysis underscored the importance of differentially expressed genes identified in the groups divided by genes participated in NETs, with enrichment analysis showing the mechanism. Correlation analysis revealed significant associations with B cells, NK cells, mast cells, T cells, plasma cells, dendritic cells, and monocytes. The IC values of drugs such as all-trans-retinoic acid (ATRA), axitinib, doxorubicin, methotrexate, sorafenib, and vinblastine were increased, while dasatinib exhibited a lower IC. A total of 13 NET-related genes were selected in constructing the risk model. In the training, testing, and merged cohorts, KM analysis demonstrated significantly improved survival for low-risk cALL patients compared to high-risk cALL patients ( < 0.001). The area under the curve (AUC) indicated strong predictive performance. Experiments in Jurkat and SUP-B15 revealed that TRIM8 knockdown decreased the proliferation of leukemia cell lines. Further experiments demonstrated a more favorable prognosis in mice with TRIM8-knockdown leukemia cells. Results of cell lines and animals showed better outcomes in prognosis when TRIM8 was knocked down.
We identified a novelty in a prognostic model that could aid in the development of personalized treatments for cALL patients. Furthermore, it revealed that the expression of TRIM8 is a contributing factor to the proliferation of leukemia cells and worsens the prognosis of cALL.
中性粒细胞胞外诱捕网（NETs）与癌细胞的转移、发生及免疫逃逸有关。我们研究了NET相关基因在儿童急性淋巴细胞白血病（cALL）患者中的预后价值。
对从公共数据库收集的样本进行差异基因表达分析。根据NET相关基因的表达水平对样本进行分组，评估免疫细胞类型与cALL预后不良风险评分之间的相关性，并评估cALL中使用的药物的敏感性。我们进一步整合生存数据对组进行划分。随后，利用多变量Cox算法、最小绝对收缩和选择算子（LASSO）以及单变量分析等方法建立预测预后的风险模型。进行细胞系和动物实验以探索模型选择的基因TRIM8的功能。为了验证TRIM8在白血病发展中的作用，在T-ALL和B-ALL小鼠中采用慢病毒介导的TRIM8过表达或敲低。
Kaplan-Meier（KM）分析强调了在按参与NETs的基因划分的组中鉴定出的差异表达基因的重要性，富集分析显示了其机制。相关性分析揭示了与B细胞、NK细胞、肥大细胞、T细胞、浆细胞、树突状细胞和单核细胞的显著关联。全反式维甲酸（ATRA）、阿昔替尼、多柔比星、甲氨蝶呤、索拉非尼和长春碱等药物的IC值升高，而达沙替尼的IC值较低。在构建风险模型时共选择了13个NET相关基因。在训练、测试和合并队列中，KM分析表明，与高危cALL患者相比，低危cALL患者的生存率显著提高（<0.001）。曲线下面积（AUC）表明具有强大的预测性能。Jurkat和SUP-B15细胞系实验表明，TRIM8敲低可降低白血病细胞系的增殖。进一步实验表明，TRIM8敲低的白血病细胞小鼠预后更佳。细胞系和动物实验结果表明，TRIM8敲低时预后更好。
我们在预后模型中发现了一个新特点，这有助于为cALL患者开发个性化治疗方案。此外，研究表明TRIM8的表达是白血病细胞增殖的一个促成因素，会使cALL的预后恶化。
