MYB Confers Sorafenib Resistance in Human Leukemia Cells via Inhibiting Ferroptosis Through FTH1 Upregulation.

BACKGROUND: MYB is a key transcription factor that plays an essential role in regulating hematopoiesis, particularly influencing cell proliferation, differentiation, and apoptosis. It has been extensively implicated in the pathogenesis and progression of leukemia, as well as in determining patient prognosis and responsiveness to chemotherapy. Despite these well-documented roles, the precise molecular mechanisms by which MYB contributes to chemotherapy resistance in leukemia remain largely undefined. METHODS: In this study, we investigated the potential role of MYB in regulating ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, which has recently emerged as a novel therapeutic target in cancer. We overexpressed and knockdown MYB in human leukemia K562 cells and evaluated changes in ferroptosis-related markers, as well as cell proliferation and migration capacities, in the context of treatment with the chemotherapeutic agent sorafenib. RESULTS: Our findings demonstrated that MYB overexpression significantly enhanced the resistance of human leukemia cells to sorafenib, while MYB knockdown increased their drug sensitivity. Mechanistically, MYB was found to upregulate ferritin heavy chain 1 (FTH1), thereby suppressing sorafenib-induced ferroptosis and cell death. Further, FTH1 knockdown significantly reduced the proliferation and migration ability of K562 cells and enhanced sorafenib-induced ferroptosis. Rescue experiments confirmed that FTH1 is required for MYB induced sorafenib resistance and ferroptosis inhibition in human leukemia cells. CONCLUSIONS: Collectively, this study identifies the MYB-FTH1 axis as a novel regulatory pathway modulating ferroptosis and chemoresistance in leukemia cells, providing potential therapeutic targets for improving treatment precision and preventing disease relapse.