Integrative multi-omics, machine learning, and experimental validation reveal that TPM1 suppresses M2 macrophage polarization and enhances chemosensitivity in acute myeloid leukemia

BACKGROUND: Acute myeloid leukemia (AML) remains a therapeutic challenge due to chemoresistance and immunosuppression. This study aimed to discover novel regulatory mechanisms in AML pathogenesis. METHODS: Integrative transcriptomic (GSE30029) and proteomic (PXD008378) analyses with machine learning (LASSO, SVM-RFE, random forest) were performed to identify core AML regulators. Functional validation was conducted in AML cell lines (HL-60, NB4), including cell proliferation and apoptosis assays, cytarabine (Ara-C) sensitivity testing, and a subcutaneous xenograft model. Macrophage polarization was evaluated in co-culture systems. Molecular mechanisms were explored via MeRIP, RIP, and mRNA stability assays. RESULTS: Tropomyosin 1 (TPM1) was identified as a potential key factor in AML. TPM1 was downregulated in AML tissues and cells. TPM1 overexpression inhibited AML cell proliferation, promoted apoptosis and oxidative stress, and enhanced sensitivity to Ara-C. Furthermore, TPM1 upregulation attenuated M2 macrophage polarization. Mechanistically, the m6A eraser fat mass and obesity-associated protein (FTO) destabilized TPM1 mRNA in an m6A-dependent manner. Downregulation of TPM1 reversed the effects of FTO depletion on AML cell proliferation, Ara-C sensitivity, and M2 macrophage polarization. CONCLUSION: This study unveils a novel FTO/m6A/TPM1 axis that coordinately governs AML cell growth, chemosensitivity, and macrophage polarization, highlighting it as a promising therapeutic target.