BackgroundAcute myeloid leukemia (AML) is a common hematologic malignancy characterized by poor prognoses and high recurrence rates. Mitochondrial metabolism has been increasingly recognized to be crucial in tumor progression and treatment resistance. The purpose of this study was to examined the role of mitochondrial metabolism in the immune regulation and prognosis of AML.MethodsIn this study, mutation status of 31 mitochondrial metabolism-related genes (MMRGs) in AML were analyzed. Based on the expression of 31 MMRGs, mitochondrial metabolism scores (MMs) were calculated by single sample gene set enrichment analysis. Differential analysis and weighted co-expression network analysis were performed to identify module MMRGs. Next, univariate Cox regression and the least absolute and selection operator regression were used to select prognosis-associated MMRGs. A prognosis model was then constructed using multivariate Cox regression to calculate risk score. We validated the expression of key MMRGs in clinical specimens using immunohistochemistry (IHC). Then differential analysis was performed to identify differentially expressed genes (DEGs) between high- and low-risk groups. Functional enrichment, interaction networks, drug sensitivity, immune microenvironment, and immunotherapy analyses were also performed to explore the characteristic of DEGs.ResultsGiven the association of MMs with prognosis of AML patients, a prognosis model was constructed based on 5 MMRGs, which could accurately distinguish high-risk patients from low-risk patients in both training and validation datasets. IHC results showed that MMRGs were highly expressed in AML samples compared to normal samples. Additionally, the 38 DEGs were mainly related to mitochondrial metabolism, immune signaling, and multiple drug resistance pathways. In addition, high-risk patients with more immune-cell infiltration had higher Tumor Immune Dysfunction and Exclusion scores, indicating poor immunotherapy response. mRNA-drug interactions and drug sensitivity analyses were performed to explore potential druggable hub genes. Furthermore, we combined risk score with age and gender to construct a prognosis model, which could predict the prognosis of AML patients.ConclusionOur study provided a prognostic predictor for AML patients and revealed that mitochondrial metabolism is associated with immune regulation and drug resistant in AML, providing vital clues for immunotherapies.

中文翻译：

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急性髓性白血病线粒体代谢相关基因的综合生物信息学分析

背景急性髓性白血病（AML）是一种常见的血液系统恶性肿瘤，其特点是预后差和复发率高。人们越来越认识到线粒体代谢在肿瘤进展和治疗耐药性中起着至关重要的作用。本研究旨在探讨线粒体代谢在AML免疫调节及预后中的作用。方法本研究分析了AML中31个线粒体代谢相关基因（MMRGs）的突变状态。基于 31 个 MMRG 的表达，通过单样本基因集富集分析计算线粒体代谢评分 (MM)。进行差异分析和加权共表达网络分析以识别模块 MMRG。下一个，使用单变量 Cox 回归和最小绝对值和选择算子回归来选择预后相关的 MMRG。然后使用多变量 Cox 回归构建预后模型以计算风险评分。我们使用免疫组织化学 (IHC) 验证了临床标本中关键 MMRG 的表达。然后进行差异分析以确定高风险组和低风险组之间的差异表达基因（DEG）。还进行了功能富集、相互作用网络、药物敏感性、免疫微环境和免疫治疗分析，以探索 DEGs 的特征。结果鉴于 MMs 与 AML 患者预后的关联，基于 5 个 MMRGs 构建了预后模型，这可以在训练和验证数据集中准确地区分高风险患者和低风险患者。IHC 结果显示，与正常样本相比，MMRG 在 AML 样本中高表达。此外，这38个DEGs主要与线粒体代谢、免疫信号和多种耐药途径有关。此外，免疫细胞浸润较多的高危患者肿瘤免疫功能障碍和排除评分较高，表明免疫治疗反应较差。进行了 mRNA-药物相互作用和药物敏感性分析，以探索潜在的可药物中枢基因。此外，我们将风险评分与年龄和性别相结合，构建了一个预后模型，可以预测 AML 患者的预后。