Identification and Validation of Plasma Protein Biomarkers as Therapeutic Targets in Acute Myeloid Leukemia: An Integrative Multi-omics Study

Linhui Hu^1*Qingqing Luo¹Ya Liao²Zhimin Zhai²Yangyang Ding²Yan Fei¹

• ¹Second Affiliated Hospital of Nanchang University, Nanchang, China
• ²Second Affiliated Hospital of Anhui Medical University, Hefei, China

Acute myeloid leukemia (AML) remains a therapeutic challenge due to its high relapse rate and limited treatment options. Using an integrative multi-omics approach, we aimed to identify and validate novel circulating protein biomarkers with causal roles in AML pathogenesis. We performed proteome-wide Mendelian randomization (MR) analyses utilizing pQTL data from two large-scale proteomic studies (deCODE and UK Biobank Pharma Proteomics Project) and GWAS data from two cohorts (FinnGen and UK Biobank). Three independent MR analyses identified TNFAIP8, TCL1A, and WFDC1 as risk factors for AML, while TNFSF8 was identified as a protective factor. Single-cell RNA sequencing revealed distinct expression patterns of these proteins within hematopoietic progenitor and immune cells, suggesting roles in microenvironmental dysregulation. Experimental validation via ELISA confirmed elevated levels of TNFAIP8, TCL1A, and WFDC1 and reduced levels of TNFSF8 in AML patients compared to healthy controls. Furthermore, dynamic changes in TNFAIP8 (increase at relapse) and TNFSF8 (recovery during remission) highlighted their potential as biomarkers for disease monitoring. Drug repurposing analysis prioritized 13 candidates targeting these proteins, including FDA-approved agents, and phenome-wide association studies supported their safety profiles. This study provides the first genetic evidence supporting the causal roles of these plasma proteins in AML, offering new insights for targeted therapy development and relapse monitoring.