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bioRxiv · 10.64898/2025.12.24.696467

Transcriptomic Profiling Reveals Key Molecular Events and Pathways Driving Acquired Chemotherapy Resistance in Relapsed Acute Myeloid Leukemia

Hu, J.·Wan, B.·Shi, J.·Zou, M.·He, C.
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Abstract

BackgroundAcute myeloid leukemia (AML) is a highly heterogeneous hematologic malignancy. Although induction therapy induces remission in many patients, relapse and acquired chemoresistance remain the major causes of treatment failure. Defining the molecular mechanisms underlying relapse is essential for improving therapeutic strategies. MethodsBone marrow samples from nine AML patients were analyzed, including five newly diagnosed cases and four relapsed cases after chemotherapy. Transcriptome sequencing and integrative bioinformatics analyses were performed, including differential expression analysis, GO/KEGG enrichment, GSEA, and protein-protein interaction (PPI) network analysis, to delineate relapse-associated molecular alterations. ResultsPrincipal component analysis demonstrated clear transcriptional segregation between primary and relapsed AML, indicating extensive molecular reprogramming during relapse. A total of 2,025 differentially expressed genes were identified, enriched in pathways related to epithelial-mesenchymal transition-like programs, leukemia stem cell maintenance, apoptosis evasion, and bone marrow microenvironment remodeling. Marked upregulation of FOXC1, HOXA11/HOXA11-AS, and AXL suggests key roles in sustaining stemness and promoting drug resistance. GO/KEGG analysis revealed coordinated activation of small GTPase, Rho/Ras signaling, ion transport, and epigenetic regulatory pathways, reflecting multilayered adaptive responses. GSEA indicated metabolic-epigenetic reprogramming in relapsed AML, while primary AML showed enrichment of energy metabolism and chromatin assembly pathways. PPI network analysis highlighted a central inflammation-metabolism axis involving TP53, IL6, CXCL8, and CCL2, associated with apoptosis resistance and metabolic adaptation. ConclusionsRelapsed AML is characterized by transcriptional reprogramming, metabolic remodeling, and microenvironment-driven adaptive resistance. Targeting small GTPase signaling, AXL, or IL6-related inflammatory pathways, alone or combined with epigenetic modulators, may offer promising therapeutic strategies to overcome chemoresistance in AML.

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Hu, J., Wan, B., Shi, J., Zou, M., He, C.. 2025-12-26. Transcriptomic Profiling Reveals Key Molecular Events and Pathways Driving Acquired Chemotherapy Resistance in Relapsed Acute Myeloid Leukemia. https://doi.org/10.64898/2025.12.24.696467

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