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

ABSTRACT: 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/β-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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE283851 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:Surface expression of C-X-C chemokine receptor type 4 (CXCR4) in acute myeloid leukemia (AML) has been reported to be an independent prognostic factor for disease relapse and survival. We previously reported that targeting the stromal-derived factor 1M-NM-1 (SDF-1M-NM-1)/CXCR4 axis could overcome resistance of AML cells to chemotherapy both in vitro and in vivo. To further explore the mechanism of targeting CXCR4, in the current study we focused on the regulation of microRNA. Microarray analysis revealed that the hsa-let-7a microRNA was down-regulated in OCI-AML3 cells by SDF-1M-NM-1 treatment and increased after CXCR4 inhibition. To further investigate the role of hsa-let-7a in leukemia biology, we overexpressed it in AML cell lines, which resulted in decreased Bcl-xL protein expression and consequently enhanced cell sensitivity to the chemotherapeutic agent cytarabine, both in vitro and in vivo. We also identified the transcription factor Yin Yang 1 (YY1) as a mediator that links the SDF-1M-NM-1/CXCR4 axis with hsa-let-7a. Western blotting and immunocytochemistry demonstrated a correlation between YY1 and CXCR4 activation. ChIP assay confirmed the binding of YY1 to pri-let-7a DNA fragments. In primary AML samples (n=50), high CXCR4 surface expression was associated with low hsa-let-7a levels (r2=0.53). Improved effects of cytarabine treatment associated with greatly extended survival of human AML carrying mice was observed in primary human AML overexpressing hsa-let-7a. On the basis of these results, we propose that CXCR4 regulation of hsa-let-7a microRNA through YY1 and transcriptional silencing of the Bcl-xL protein together identifies a novel mechanism by which CXCR4 functions to induce chemoresistance in AML cells. MicroRNA expression profiling of OCI-AML3 cell lines treated with CXCR4 antagonist or SDF-1M-NM-1. OCI-AML3 cells were treated with 100 ng/mL SDF-1M-NM-1 or 250 nM POL6326 (a CXCR4 antagonist, Allschwil, Switzerland), total RNA was extracted at specific time points (1, 2, 4, and 8 h), and miRNA expression profiling was performed

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

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