Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China.
Clin Transl Oncol. 2023 Aug;25(8):2393-2407. doi: 10.1007/s12094-023-03118-4. Epub 2023 Feb 24.
Recent studies have reported that cuproptosis, a novel cell death pathway, strongly correlates with mitochondrial metabolism. In addition, the studies reported that cuproptosis plays a role in the development of several cancers and is regulated by protein lipoylation. During cuproptosis, copper binds to the lipoylated proteins and mediates cancer progression. However, the role of cuproptosis in acute myeloid leukemia (AML) patients is yet to be explored.
This study curated seven cuproptosis-related-genes (CRGs): FDX1, DLAT, PDHB, PDHA1, DLD, LIAS, and LIPT1 to determine cuproptosis modification patterns and the CRGs signature in AML. The CIBERSORT and ssGSEA algorithms were utilized to evaluate the infiltration levels of different immune cell subtypes. A cuproptosis score system based on differentially expressed genes (DEGs) was constructed using the least absolute shrinkage and selection operator (LASSO) regression analysis. The developed cuproptosis score system was validated using two immunotherapy datasets, IMvigor210 and GSE78220.
Three distinct cuproptosis regulation patterns were identified using the Beat AML cohort. The results demonstrated that the three cuproptosis regulation patterns were correlated with various biological pathways and clinical outcomes. Tumor microenvironment (TME) characterization revealed that the identified cuproptosis regulation patterns were consistent with three immune profiles: immune-desert, immune-inflamed, and immune-excluded. The AML patients were grouped into low- and high-score groups based on the cuproptosis score system abstracted from 486 cuproptosis-related DEGs. Patients with lower cuproptosis scores were characterized by longer survival time and attenuated immune infiltration. It was found that lower cuproptosis scores were strongly correlated with lower somatic mutation frequency. Moreover, patients with lower cuproptosis scores presented more favorable immune responses and dual clinical benefits among external validation cohorts.
Cuproptosis phenotypes are significantly correlated with immune microenvironment complexity and variety. Cuprotopsis regulates the response of cancer cells to the immune system. Quantitatively assessing cuproptosis phenotypes in AML improves the understanding and knowledge regarding immune microenvironment characteristics and promotes the development of therapeutic interventions.
最近的研究表明，细胞铜死亡途径与线粒体代谢密切相关。此外，研究表明细胞铜死亡在多种癌症的发展中发挥作用，并受蛋白 lipoylation 调控。在细胞铜死亡过程中，铜与 lipoylated 蛋白结合并介导癌症进展。然而，细胞铜死亡在急性髓系白血病（AML）患者中的作用尚未得到探索。
本研究通过 curate 七个与细胞铜死亡相关的基因（CRGs）：FDX1、DLAT、PDHB、PDHA1、DLD、LIAS 和 LIPT1，确定 AML 中的细胞铜死亡修饰模式和 CRGs 特征。利用 CIBERSORT 和 ssGSEA 算法评估不同免疫细胞亚群的浸润水平。使用最小绝对收缩和选择算子（LASSO）回归分析构建基于差异表达基因（DEGs）的细胞铜死亡评分系统。使用两个免疫治疗数据集 IMvigor210 和 GSE78220 对开发的细胞铜死亡评分系统进行验证。
使用 Beat AML 队列鉴定了三种不同的细胞铜死亡调控模式。结果表明，三种细胞铜死亡调控模式与多种生物学途径和临床结局相关。肿瘤微环境（TME）特征分析表明，鉴定的细胞铜死亡调控模式与三种免疫特征一致：免疫荒漠、免疫炎症和免疫排斥。根据 486 个与细胞铜死亡相关的 DEGs 提取的细胞铜死亡评分系统，将 AML 患者分为低评分组和高评分组。低评分组患者的生存时间更长，免疫浸润减弱。发现较低的细胞铜死亡评分与较低的体细胞突变频率密切相关。此外，低评分组患者表现出更好的免疫反应和双重临床获益，这在外部验证队列中得到了验证。
细胞铜死亡表型与免疫微环境的复杂性和多样性显著相关。细胞铜死亡调节癌细胞对免疫系统的反应。定量评估 AML 中的细胞铜死亡表型可以提高对免疫微环境特征的理解和认识，并促进治疗干预措施的发展。
