Somatic mutation-associated risk index based on lncRNA expression for predicting prognosis in acute myeloid leukemia

<b>Objectives:</b> Genomic instability has several implications for acute myeloid leukemia (AML) prognosis. This article aims to construct a somatic mutation-associated risk index (SMRI) of genomic instability for AML to predict prognosis and explore the potential determinants of AML prognosis. <b>Methods:</b> We obtained differentially expressed lncRNAs from genomic instability subtypes and selected six lncRNAs to construct the SMRI through multivariate Cox regression analysis. The median SMRI classified patients into high and low SMRI groups. Kaplan–Meier survival analysis was used to clarify the prognostic differences of SMRI subtypes. Receiver operating characteristic curve analysis was performed to elucidate the value of SMRI as a prognostic indicator. Gene set variation analysis, tumor mutation burden (TMB) analysis, immune infiltration, and immune checkpoint expression analysis were performed to investigate possible causes for the differences in prognosis of SMRI subtypes. <b>Results:</b> The high SMRI group exhibited a poor prognosis, which was characterized by elevated levels of TMB, mutation counts (TP53, NPM1, DNMT3A, and FLT3-TKD), CD8⁺ T cell infiltration, and immune checkpoint (PD-1, PD-L2, CTLA4, LAG3) expression. The SMRI was still associated with prognosis, even after adjustment for age, sex, cytogenetic risk, DNMT3A status, FLT3 status, and NPM1 status. Gene set variation analysis showed that AML with FLT3-ITD mutation, CEBPA mutation, and LSCs (leukemia stem cells) were enriched in the high SMRI group. <b>Conclusion:</b> Our research suggests that the SMRI derived from genomic instability subtypes is a useful biomarker for predicting prognosis and may be beneficial for improving the clinical outcome of patients with AML.

**研究目的：** 基因组不稳定性对急性髓系白血病（acute myeloid leukemia, AML）的预后具有多重影响。本研究旨在构建与AML基因组不稳定性相关的体细胞突变相关风险指数（somatic mutation-associated risk index, SMRI）以预测患者预后，并探讨AML预后的潜在影响因素。
**研究方法：** 我们从基因组不稳定性亚型中获取差异表达长链非编码RNA（long non-coding RNA, lncRNA），并通过多因素Cox回归分析筛选出6个lncRNA以构建SMRI。以SMRI的中位数为截点将患者划分为高SMRI组与低SMRI组。采用Kaplan-Meier生存分析明确SMRI分型的预后差异；通过受试者工作特征曲线分析阐明SMRI作为预后指标的临床价值。此外，我们开展基因集变异分析、肿瘤突变负荷（tumor mutation burden, TMB）分析、免疫浸润分析及免疫检查点表达分析，以探究SMRI分型预后差异的潜在机制。
**研究结果：** 高SMRI组患者预后较差，其特征为肿瘤突变负荷升高、TP53、NPM1、DNMT3A及FLT3-TKD突变数增加、CD8⁺ T细胞浸润程度升高，且PD-1、PD-L2、CTLA4、LAG3等免疫检查点分子表达水平上调。在校正年龄、性别、细胞遗传学风险、DNMT3A状态、FLT3状态及NPM1状态后，SMRI仍与患者预后显著相关。基因集变异分析显示，携带FLT3-ITD突变、CEBPA突变的AML及白血病干细胞（leukemia stem cells, LSCs）相关基因集在高SMRI组中显著富集。
**研究结论：** 本研究表明，基于基因组不稳定性亚型构建的SMRI是预测AML患者预后的有效生物标志物，或可用于改善AML患者的临床诊疗结局。