Mechanism of METTL3 promoting rituximab resistance via β-catenin/MYC axis in double-expressor diffuse large B cell lymphoma.

OBJECTIVE

To explore how methyltransferase-like 3 (METTL3) regulates myelocytomatosis oncogene (MYC)/B-cell lymphoma 2 (BCL2) transcriptional expression via YTHDF2-mediated m6A modification of β-catenin, thereby influencing rituximab (RTX) resistance in double-expressor diffuse large B-cell lymphoma (DE-DLBCL).

METHODS

DE-DLBCL cells (U-2932) were cultured in vitro, followed by si-METTL3, oe-β-catenin, oe-MYC, oe-BLC2, or RTX treatment. SRAMP database predicted m6A sites in β-catenin. MeRIP-qPCR and RIP were performed to detect m6A enrichment in β-catenin and YTHDF2 enrichment in β-catenin mRNA. The stability of β-catenin mRNA was assessed using actinomycin D. The interaction between MYC and BCL2 was predicted by JASPAR database and confirmed by dual luciferase assay and ChIP. Finally, a DE-DLBCL nude mouse model was established and treated with RTX and METTL3 inhibitor (STM2457). Tumor growth and related molecule expression were evaluated.

RESULTS

U-2932 cells exhibited high expression of MYC and BCL2, elevated METTL3 levels, and increased cell viability. Cell cycle progression was accelerated, manifested by decreased cells in the G0-G1 phase, increased cells in S and G2-M phases, elevated cell proliferation, and enhanced RTX resistance. METTL3 knockdown inhibited cell cycle and RTX resistance in DE-DLBCL cells. METTL3 promoted β-catenin expression via m6A modification. METTL3 activated MYC and BCL2 indirectly. METTL3 inhibition suppressed DE-DLBCL cell growth and RTX resistance via the β-catenin/MYC axis in vivo.

CONCLUSION

METTL3 may drive DE-DLBCL cell cycle progression and RTX resistance by activating MYC and BCL2 transcription via YTHDF2-mediated m6A modification of β-catenin, revealing a novel mechanism of indirect transcriptional regulation in lymphoma and a potential therapeutic target.