Biochimica et biophysica acta. Molecular basis of disease · 2026
Exosomal METTL16 from mesenchymal stem cells promotes malignant progression and M2 macrophage polarization in acute myeloid leukemia via IGF2BP2-dependent GPX1 m6A modification.
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Shang Zhen, Zhou Mi, Yan Sijia, Su Shuai, Zheng Rubing, Wang Yu, Xiao Yi
Аннотация
BACKGROUND: Acute myeloid leukemia (AML) progression relies on complex crosstalk with the bone marrow microenvironment, particularly M2 macrophage polarization. Exosomes mediate intercellular communication, while N6-methyladenosine (m6A) modifications drive tumor malignancy. However, the role of exosomal m6A regulators in coordinating AML progression and macrophage polarization remains unclear.
METHODS: Integrated bioinformatics combining transcriptomics, weighted gene co-expression network analysis (WGCNA), and single-cell RNA sequencing identified key genes in AML. mRNA and protein expression levels were detected by quantitative real-time polymerase chain reaction and Western blotting assays. In vitro assays evaluated AML cell proliferation, apoptosis, oxidative stress, and drug sensitivity. Macrophage polarization was assessed using Transwell co-culture systems. Exosome isolation, m6A RNA immunoprecipitation, RNA immunoprecipitation, and dual-luciferase reporter assays elucidated the underlying molecular mechanism. A xenograft mouse model assay was performed to analyze the effects of methyltransferase-like 16 (METTL16)-deficient exosomes and glutathione peroxidase 1 (GPX1) overexpression on tumor formation.
RESULTS: GPX1 was identified as a hub gene in AML. Its expression was significantly upregulated in AML and closely linked to monocyte-macrophage differentiation. Functionally, GPX1 silencing suppressed AML cell malignancy, induced oxidative stress, enhanced cytarabine sensitivity, and inhibited M2 polarization (P < 0.05). Mechanistically, METTL16 mediated GPX1 m6A modification, which was recognized by insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) to stabilize GPX1 mRNA (P < 0.05). Notably, METTL16 was highly enriched in both AML patient serum-derived exosomes and AML-mesenchymal stem cell (MSC)-derived exosomes (P < 0.05). METTL16-deficient exosomes effectively reversed these pro-tumoral effects both in vitro and in vivo by downregulating GPX1 (P < 0.05).
CONCLUSION: Exosomal METTL16 from AML-MSCs plays a crucial role in promoting leukemic cell survival and M2 polarization. Targeting this axis may provide a potential theoretical foundation to reverse M2 macrophage polarization and inhibit AML progression.
METHODS: Integrated bioinformatics combining transcriptomics, weighted gene co-expression network analysis (WGCNA), and single-cell RNA sequencing identified key genes in AML. mRNA and protein expression levels were detected by quantitative real-time polymerase chain reaction and Western blotting assays. In vitro assays evaluated AML cell proliferation, apoptosis, oxidative stress, and drug sensitivity. Macrophage polarization was assessed using Transwell co-culture systems. Exosome isolation, m6A RNA immunoprecipitation, RNA immunoprecipitation, and dual-luciferase reporter assays elucidated the underlying molecular mechanism. A xenograft mouse model assay was performed to analyze the effects of methyltransferase-like 16 (METTL16)-deficient exosomes and glutathione peroxidase 1 (GPX1) overexpression on tumor formation.
RESULTS: GPX1 was identified as a hub gene in AML. Its expression was significantly upregulated in AML and closely linked to monocyte-macrophage differentiation. Functionally, GPX1 silencing suppressed AML cell malignancy, induced oxidative stress, enhanced cytarabine sensitivity, and inhibited M2 polarization (P < 0.05). Mechanistically, METTL16 mediated GPX1 m6A modification, which was recognized by insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) to stabilize GPX1 mRNA (P < 0.05). Notably, METTL16 was highly enriched in both AML patient serum-derived exosomes and AML-mesenchymal stem cell (MSC)-derived exosomes (P < 0.05). METTL16-deficient exosomes effectively reversed these pro-tumoral effects both in vitro and in vivo by downregulating GPX1 (P < 0.05).
CONCLUSION: Exosomal METTL16 from AML-MSCs plays a crucial role in promoting leukemic cell survival and M2 polarization. Targeting this axis may provide a potential theoretical foundation to reverse M2 macrophage polarization and inhibit AML progression.