Abstract

Ibrutinib resistance remains a major obstacle in the treatment of diffuse large B-cell lymphoma (DLBCL). Fat mass and obesity-associated protein (FTO) has been implicated in drug resistance through its regulation of N6-methyladenosine (m6A) modifications; however, whether FTO mediates ibrutinib resistance in DLBCL remains unclear. In this study, we found that FTO expression was significantly upregulated in patient samples and DLBCL cell lines. Functional assays showed that FTO knockout or knockdown suppressed cell proliferation and colony formation, whereas FTO overexpression promoted tumor growth and increased ibrutinib half-maximal inhibitory concentration. Mechanistically, FTO directly bound to myelocytomatosis oncogene (Myc) mRNA and removed m6A modifications, stabilizing Myc transcripts and enhancing Myc protein expression. Methylated RNA immunoprecipitation–quantitative polymerase chain reaction confirmed that FTO knockout increased m6A enrichment on Myc mRNA, leading to decreased Myc stability. Rescue experiments showed that reintroducing Myc partially restored the proliferative and drug-resistant phenotype of FTO-deficient cells. Consistently, in xenograft models, FTO promoted tumor growth and ibrutinib resistance in a manner partly dependent on Myc. Overall, FTO promotes DLBCL progression and ibrutinib resistance by demethylating Myc mRNA and stabilizing its expression. These findings highlight the FTO-m6A-Myc axis as a potential therapeutic target for overcoming drug resistance in DLBCL.