SRC as a Prognostic and Immunomodulatory Biomarker in Acute Myeloid Leukemia: A Multi-Omics Study

The bone marrow tumor microenvironment (TME) is critical for acute myeloid leukemia (AML) progression, immune evasion, and treatment resistance. SRC, a non-receptor tyrosine kinase involved in multiple oncogenic pathways, has not been systematically characterized in AML in relation to prognosis and immune regulation. We integrated bulk transcriptomic and single-cell RNA-sequencing datasets from TCGA, BeatAML, and GEO. Immune-related targets were identified using xCell-based immune scoring and weighted gene co-expression network analysis (WGCNA), followed by protein–protein interaction analysis and multi-algorithm machine-learning screening. We then evaluated SRC expression patterns, prognostic associations, immune microenvironment features, predicted drug sensitivity, single-cell differentiation dynamics, intercellular communication, and in silico virtual knockout perturbation (scTenifoldKnk). SRC emerged as the most robust hub gene after integration of WGCNA, PPI analysis, machine-learning feature selection, and survival screening. SRC was significantly upregulated in AML compared with normal controls and was independently associated with poor overall survival (HR = 1.231, p = 0.037). High SRC expression was linked to adverse ELN/FAB features, increased immune checkpoint expression, enrichment of inflammatory and immunoregulatory pathways, and a higher proportion of primitive leukemia-associated cell states. Single-cell analyses further suggested that SRC was enriched in CD34+ progenitor compartments, associated with altered cell–cell communication, and accompanied by distinct mutation and pathway profiles. Drug-response prediction and in silico network perturbation analysis further supported the potential biological and translational relevance of SRC-centered programs. SRC is a prognostically relevant and immune-associated hub linked to AML microenvironment remodeling, and may serve as a candidate biomarker and potential therapeutic target that warrants further experimental validation.