■中性粒细胞胞外陷阱(NETs)可归因于转移,发生,和癌细胞的免疫逃避。我们调查了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品进行差异基因表达分析。根据NET相关基因的表达水平对它们进行分组,我们评估了免疫细胞类型与cALL预后不良的风险评分之间的相关性,评估cALL中使用的药物的敏感性。我们进一步划分了小组,整合生存数据。随后,方法包括多变量Cox算法,最小绝对收缩和选择运算符(LASSO),并利用单变量建立预测预后的风险模型。在细胞系和动物中进行实验以探索通过模型选择的基因TRIM8的功能。为了验证TRIM8在白血病发展中的作用,在具有T-ALL和B-ALL的小鼠中采用慢病毒介导的TRIM8的过表达或敲低。
■Kaplan-Meier(KM)分析强调了在由参与NET的基因划分的组中鉴定的差异表达基因的重要性,富集分析显示了机理。相关分析显示与B细胞显著相关,NK细胞,肥大细胞,T细胞,浆细胞,树突状细胞,和单核细胞。全反式维甲酸(ATRA)等药物的IC50值,阿西替尼,阿霉素,甲氨蝶呤,索拉非尼,和长春碱增加,而达沙替尼表现出较低的IC50。共选取13个NET相关基因构建风险模型。在训练中,测试,和合并的队列,KM分析表明,与高风险cALL患者相比,低风险cALL患者的生存率显着提高(p<0.001)。曲线下面积(AUC)表明强预测性能。Jurkat和SUP-B15的实验表明,TRIM8敲低可降低白血病细胞系的增殖。进一步的实验证明在具有TRIM8敲低白血病细胞的小鼠中更有利的预后。当TRIM8被击倒时,细胞系和动物的结果显示预后更好。
■我们发现了一种新颖的预后模型,可以帮助开发cALL患者的个性化治疗方法。此外,提示TRIM8的表达是白血病细胞增殖的一个促进因素,并使cALL的预后恶化。
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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 IC50 values of drugs such as all-trans-retinoic acid (ATRA), axitinib, doxorubicin, methotrexate, sorafenib, and vinblastine were increased, while dasatinib exhibited a lower IC50. 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 (p < 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.
UNASSIGNED: 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.