Background: Acute myeloid leukemia (AML) is one of the most common malignant and aggressive hematologic tumors, and its pathogenesis is associated with abnormal post-transcriptional regulation. Unbalanced competitive endogenous RNA (ceRNA) promotes tumorigenesis and progression, and greatly contributes to tumor risk classification and prognosis. However, the comprehensive analysis of the circular RNA (circRNA)-long non-coding RNA (lncRNA)-miRNA-mRNA ceRNA network in the prognosis of AML is still rarely reported. Method: We obtained transcriptome data of AML and normal samples from The Cancer Genome Atlas (TCGA), Genotype-tissue Expression (GTEx), and Gene Expression Omnibus (GEO) databases, and identified differentially expressed (DE) mRNAs, lncRNAs, and circRNAs. Then, the targeting relationships among lncRNA-miRNA, circRNA-miRNA, and miRNA-mRNA were predicted, and the survival related hub mRNAs were further screened by univariate and multivariate Cox proportional hazard regression. Finally, the AML prognostic circRNA-lncRNA-miRNA-mRNA ceRNA regulatory network was established. Results: We identified prognostic 6 hub mRNAs (TM6SF1, ZMAT1, MANSC1, PYCARD, SLC38A1, and LRRC4) through Cox regression model, and divided the AML samples into high and low risk groups according to the risk score obtained by multivariate Cox regression. Survival analysis verified that the survival rate of the high-risk group was significantly reduced (p < 0.0001). The prognostic ceRNA network of 6 circRNAs, 32 lncRNAs, 8 miRNAs, and 6 mRNAs was established according to the targeting relationship between 6 hub mRNAs and other RNAs. Conclusion: In this study, ceRNA network jointly participated by circRNAs and lncRNAs was established for the first time. It comprehensively elucidated the post-transcriptional regulatory mechanism of AML, and identified novel AML prognostic biomarkers, which has important guiding significance for the clinical diagnosis, treatment, and further scientific research of AML.

中文翻译：

---

鉴定circRNA-lncRNA-miRNA-mRNA竞争性内源RNA网络作为急性髓系白血病新的预后标志物

背景：急性髓系白血病（AML）是最常见的恶性和侵袭性血液肿瘤之一，其发病机制与异常的转录后调控有关。不平衡的竞争性内源性 RNA (ceRNA) 促进肿瘤发生和进展，对肿瘤风险分类和预后有很大贡献。然而，关于环状RNA（circRNA）-长链非编码RNA（lncRNA）-miRNA-mRNA ceRNA网络在AML预后中的综合分析仍鲜有报道。方法：我们从癌症基因组图谱 (TCGA)、基因型组织表达 (GTEx) 和基因表达综合 (GEO) 数据库中获取 AML 和正常样本的转录组数据，并鉴定了差异表达 (DE) mRNA、lncRNA 和 circRNA . 然后，lncRNA-miRNA、circRNA-miRNA、和 miRNA-mRNA 被预测，并通过单变量和多变量 Cox 比例风险回归进一步筛选与生存相关的中心 mRNA。最后，建立了AML预后circRNA-lncRNA-miRNA-mRNA ceRNA调控网络。结果：我们通过Cox回归模型确定了具有预后意义的6个枢纽mRNA（TM6SF1、ZMAT1、MANSC1、PYCARD、SLC38A1和LRRC4），并根据多元Cox回归获得的风险评分将AML样本分为高风险组和低风险组。生存分析证实，高危组的生存率显着降低（p < 0.0001）。根据6个hub mRNAs与其他RNAs的靶向关系建立了6个circRNAs、32个lncRNAs、8个miRNAs和6个mRNAs的预后ceRNA网络。结论：在本研究中，首次建立了circRNA和lncRNA共同参与的ceRNA网络。全面阐明了AML的转录后调控机制，鉴定了新的AML预后生物标志物，对AML的临床诊断、治疗和进一步科学研究具有重要的指导意义。