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.