Inflammatory Network Remodeling in AML Is Driven by Neutrophil-Centric Self-Amplifying Circuits

Acute myeloid leukemia (AML) progression involves remodeling of the bone marrow inflammatory microenvironment, yet prior studies have focused on individual cytokines rather than coordinated network-level communication. This study aimed to systematically map inflammatory network reprogramming in AML and develop a network-derived prognostic tool. Single-cell RNA sequencing was performed on bone marrow samples from three newly diagnosed AML patients and six healthy donors (47,525 cells); ligand–receptor communication was then analyzed using CellChat. Communication dominance shifted from T-cells to myeloid populations, with networks restructured into neutrophil-centric computationally predicted self-amplifying circuits, exemplified by CXCL8–CXCR2 and CCL3–CCR1 axes. Despite the limited sample size of the scRNA-seq cohort (3 AML patients and 6 healthy donors), which may limit the generalizability of the detailed cellular and network findings, the subsequent protein-level Luminex validation in a larger cohort of 46 patients and 26 healthy controls provides robust support for the key findings. An inflammatory risk score (IRS) was constructed using LASSO-penalized Cox regression and evaluated for prognostic performance and integration with the European LeukemiaNet 2022 (ELN2022) classification. Luminex profiling confirmed dysregulation of key mediators, including reduced CCL3, CCL4, CXCL8, and IL-1A together with elevated CXCL10 in AML, and revealed substantial de-modularization of the cytokine correlation network. The IRS, based on CXCL8, CCL2, and IL-1A, achieved a concordance index of 0.729 for overall survival and stratified the ELN2022 intermediate-risk category into distinct prognostic subgroups. Inflammatory network pattern analysis provides a complementary dimension to genetic risk stratification in AML. The IRS captures microenvironment-derived prognostic information not reflected by current classification systems, though prospective multicenter validation is essential before clinical application.