Cuproptosis-related lncRNAs forecast the prognosis of acute myeloid leukemia.
Cuproptosis-related lncRNAs forecast the prognosis of acute myeloid leukemia.
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DOI：
10.21037/tcr-22-2526
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发表时间：
2023-05-31
影响因子：
0.9
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中科院分区：
文献类型：
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急性髓系白血病（AML）是一种高度异质性的血液系统恶性肿瘤。白血病干细胞（LSC）是 AML 持续存在和复发的罪魁祸首之一。铜诱导的细胞死亡（即铜凋亡）的发现为 AML 的治疗提供了光明的见解。与铜离子类似，长非编码 RNA (lncRNA) 不是 AML 进展的旁观者，特别是对于 LSC 生理学。揭示铜凋亡相关的 lncRNA 在 AML 中的参与将有利于临床管理。通过 Pearson 相关分析和单变量 Cox 分析以及癌症基因组图谱-急性髓系白血病 (TCGA-LAML) 队列的 RNA 测序数据来检测与预后相关的铜凋亡相关 lncRNA。经过最小绝对收缩和选择算子（LASSO）回归以及随后的多变量Cox分析，得出铜凋亡相关风险评分（CuRS）系统来权衡AML患者的风险。此后，AML患者根据风险属性分为两组，并通过主成分分析（PCA）、风险曲线、Kaplan-Meier生存分析、组合受试者工作特征（ROC）曲线和列线图进行验证。 GSEA 和 CIBERSORT 算法分别解决了组间生物途径的变化以及免疫浸润和免疫相关过程的差异。还仔细检查了对化疗的反应。通过实时定量聚合酶链式反应（RT-qPCR）检查候选lncRNA的表达谱，并通过转录组分析确定lncRNA FAM30A的具体机制。我们构建了一个名为 CuRS 的有效预后特征，其中包含与免疫环境和化疗反应性相关的 4 个 lncRNA（TRAF3IP2-AS1、NBR2、TP53TG1 和 FAM30A）。 lncRNA FAM30A 与增殖、迁移能力、柔红霉素耐药性及其与 AUF1 的相互作用的相关性在 LSC 细胞系中得到了证明。转录组分析表明 FAM30A 与 T 细胞分化和信号传导、细胞间连接基因之间存在相关性。预后特征 CuRS 可以指导预后分层和个性化 AML 治疗。 FAM30A 的分析为研究 LSC 靶向疗法奠定了基础。
Acute myeloid leukemia (AML) is a highly heterogeneous cluster of hematologic malignancies. Leukemic stem cells (LSCs) are one of the culprits for the persistence and relapse of AML. The discovery of copper-induced cell death, namely cuproptosis, gives bright insights into the treatment of AML. Analogous to copper ions, long non-coding RNAs (lncRNAs) are not bystanders for AML progression, especially for LSC physiology. Uncovering the involvement of cuproptosis-related lncRNAs in AML will benefit clinical management. Detection of prognostic relevant cuproptosis-related lncRNAs are carried out by Pearson correlation analysis and univariate Cox analysis with RNA sequencing data of The Cancer Genome Atlas-Acute Myeloid Leukemia (TCGA-LAML) cohort. After the least absolute shrinkage and selection operator (LASSO) regression and the subsequent multivariate Cox analysis, a cuproptosis-related risk score (CuRS) system was derived to weigh the risk of AML patients. Thereafter, AML patients were classified into two groups by their risk property which was validated with principal component analysis (PCA), risk curves, Kaplan-Meier survival analysis, the combined receiver operating characteristic (ROC) curves, and nomogram. Variations in biological pathways and divergences in immune infiltration and immune-related processes between groups were resolved by GSEA and CIBERSORT algorism, respectively. Response to chemotherapies were scrutinized as well. The expression profiles of the candidate lncRNAs were examined by real-time quantitative polymerase chain reaction (RT-qPCR) and the specific mechanisms of lncRNA FAM30A were determined by transcriptomic analysis. We fabricated an efficient prognostic signature named CuRS incorporating 4 lncRNAs (TRAF3IP2-AS1, NBR2, TP53TG1, and FAM30A) relevant to immune environment and chemotherapy responsiveness. The relevance of lncRNA FAM30A with proliferation, migration ability, Daunorubicin resistance and its reciprocal action with AUF1 were demonstrated in an LSC cell line. Transcriptomic analysis suggested correlations between FAM30A and T cell differentiation and signaling, intercellular junction genes. The prognostic signature CuRS can guide prognostic stratification and personalized AML therapy. Analysis of FAM30A offers a foundation for investigating LSC-targeted therapies.
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