Integrated metabolomic and transcriptomic analysis identifies adipogenic differentiation of mesenchymal stem cells as a driver of chemoresistance in acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) remains a challenging hematological malignancy, with chemoresistance contributing significantly to treatment failure and relapse. The bone marrow microenvironment, particularly mesenchymal stem cells (MSCs), plays a critical role in AML cell survival and drug resistance. Although previous studies have extensively explored the MSCs differentiation, the regulatory role of the adipogenically differentiated MSCs on AML cells during co-culture remains unclear. METHODS: An indirect co-culture model was established to evaluate the impact of MSCs on the drug sensitivity of AML cells. Based on the comparable chemosensitivity trends observed among THP-1, U937, and HL-60 cells, THP-1 were selected for subsequent experiments due to their stable growth characteristics and well-established utilization. Metabolic alterations between co-cultured and monocultured THP-1 were profiled using nuclear magnetic resonance spectroscopy. Concurrently, RNA sequencing was conducted to identify differentially expressed genes and enriched signaling pathways between co-cultured and monocultured THP-1. To validate the pathway alterations identified by transcriptomic analysis, the Akt inhibitor MK-2206 was applied, and its effects were evaluated by western blotting and cell viability assays. RESULTS: The results demonstrated that AML cells co-cultured with adipogenic MSCs were less sensitive to daunorubicin and cytarabine in both in vitro and in vivo. Subsequent metabolomics analysis revealed significant alternative metabolic processes in AML cells following co-culture, specifically in the glycolysis, glutamine metabolism and lipid metabolism. Further transcriptomic profiling identified key differentially expressed genes and signaling pathways, with PI3K/Akt signaling pathway activation emerging as a contributor to the reduced chemotherapy sensitivity. Furthermore, elevated levels of IL-6 in the co-culture system suggested a role for cytokine-mediated signaling in promoting a protective microenvironment. CONCLUSIONS: This work demonstrates that the adipogenically differentiated MSCs enhance the survival and chemoresistance of AML cells by modulating metabolic and signaling pathways. It provides integrated insights into the microenvironment-driven mechanisms of AML drug resistance and presents potential therapeutic targets to enhance treatment efficacy.