Study on the Role of Neutrophil Extracellular Traps-Based Risk Model and Discriminative Gene LTF in the Prognosis of Acute Myeloid Leukemia and the Regulation of Immune Microenvironment

Yongjian Li,1,* Jingru Zhang,1– 3,* Tingting Liu,1 Di Zhang,1 Nana Wang,1 Xiaomin Liu,1 Panpan Feng,4 Juan Zhang,1 Chunyan Ji,1– 3 Jingjing Ye1– 3 1Department of Hematology, Qilu Hospital of Shandong University, Jinan, Shandong, People’s Republic of China; 2Shandong Key Laboratory of Hematological Diseases and Immune Microenvironment, Qilu Hospital of Shandong University, Jinan, Shandong, People’s Republic of China; 3Shandong Provincial Clinical Research Center for Hematological Diseases, Qilu Hospital of Shandong University, Jinan, Shandong, People’s Republic of China; 4Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jingjing Ye, Email yejingjing@sdu.edu.cn Chunyan Ji, Email jichunyan@sdu.edu.cnIntroduction: Dysregulation of neutrophil extracellular traps (NETs) formation is implicated in cancer progression, coagulation, and metastasis; however, the association with acute myeloid leukemia (AML) prognosis and the immune microenvironment remains poorly understood due to the inherent heterogeneity of NETs. This study aimed to elucidate the role of NETs-related genes in AML pathogenesis, risk stratification, and immune modulation.Methods: We employed comprehensive bioinformatics approaches to analyze NETs-related gene expression profiles from cBioPortal, UCSC Xena, and Gene Expression Omnibus (GEO) databases. A prognostic model was constructed using 16 NETs-related gene signatures, with rigorous validation performed in both internal and external cohorts. Multivariate Cox regression analyses assessed the model’s independence as a prognostic indicator for overall survival (OS), and a clinical nomogram was developed for practical application. Additionally, immune cell infiltration and microenvironment characteristics were evaluated through enrichment analyses to correlate NETs activity with immunological features.Results: The NETs-based prognostic model demonstrated robust predictive value for OS in AML patients across validation cohorts and was identified as an independent prognostic factor via multivariate Cox regression. This model enhanced existing risk stratification systems, with high NETs scores significantly associated with neutrophil enrichment and an immunosuppressive tumor microenvironment. Lactotransferrin (LTF) emerged as a pivotal NETs-related gene: its overexpression correlated strongly with adverse prognosis, poor chemotherapy response, and extensive remodeling of the immune landscape, including heightened neutrophil infiltration and immunosuppressive signatures.Discussion: Our comprehensive analysis of NETs in AML suggests that NETs have a role in the tumor microenvironment and prognosis. LTF is a promising candidate biomarker of therapy response and prognostic prediction, which may contribute to individualized clinical decision-making. Further functional validation and prospective clinical studies are warranted to translate our observations into targeted interventions and refine risk-adapted treatment protocols.Keywords: acute myeloid leukemia, neutrophil extracellular traps, prognosis, immune microenvironment, lactotransferrin