S100A9 Overexpression Drives Chemoresistance and Poor Prognosis in AML with Adavivint as a Targeted Therapeutic

Drug resistance and poor prognosis in acute myeloid leukemia (AML) are major challenges, underscoring the need for effective biomarkers and targeted therapies. In this study, we identified S100A9 as a critical biomarker for drug resistance and poor prognosis in AML through integrative bioinformatics analysis and experimental validation. Using transcriptomic datasets, single-cell sequencing, and proteomics, we demonstrated that S100A9 overexpression is enriched in drug-resistant AML cells, particularly in the M5 subtype. High S100A9 expression correlates with shorter survival and higher risk scores, establishing its role as a prognostic marker. Functional studies revealed that S100A9 promotes AML cell proliferation and chemoresistance by enhancing mitochondrial oxidative phosphorylation and maintaining redox homeostasis through interaction with thioredoxin (TXN). This axis prevents excessive reactive oxygen species (ROS) accumulation, supports cell survival, and activates the WNT/ß-catenin pathway to drive tumor growth. To explore therapeutic options, we identified Adavivint (Ada) through computational screening as a selective cytotoxic agent for S100A9-overexpressing AML cells. Ada demonstrated superior efficacy compared to standard drugs such as venetoclax and cytarabine, while showing reduced toxicity to normal bone marrow cells. In vivo, Ada significantly suppressed tumor progression and prolonged survival in murine models of S100A9-overexpressing AML. These findings highlight S100A9 as a promising therapeutic target and establish Adavivint as a potential agent to overcome chemoresistance in S100A9-positive AML, offering new avenues for improving outcomes in this challenging disease. Overall design: RNA-seq was performed on U937 and THP-1 cells following S100A9 knockdown and overexpression. Additionally, THP-1 cells transduced with either an empty vector or S100A9 overexpression lentivirus were treated with Adavivint (1 µM) for 36 hours, and gene expression profiling was conducted on these samples. These analyses aimed to investigate the gene expression profiles in response to S100A9 manipulation and Adavivint treatment.