Abstract

Multidrug resistance (MDR) remains a major obstacle in the clinical treatment of leukemia, severely limiting therapeutic efficacy and leading to poor patient outcomes. Drug efflux mediated by ATP-binding cassette (ABC) transporters represents a central mechanism driving cancer MDR. In this study, we identified ABCB6 as a critical mediator of MDR in leukemia through its role in promoting drug efflux. Using membrane-focused liquid chromatography‑tandem mass spectrometry (LC‑MS/MS) analysis of the leukemia cell line K562 and its MDR derivative K562/A02, we screened for differentially expressed transporters and identified ABCB6 as a candidate molecule. We further confirmed that ABCB6 is abundantly expressed on the plasma membrane of K562/A02 cells. Functional analyses demonstrated that altered ABCB6 expression did not significantly affect cell proliferation or apoptosis; however, targeted knockdown of ABCB6 markedly restored the sensitivity of K562/A02 cells to adriamycin (ADR) and cytosine arabinoside (Ara-C). Mechanistic studies revealed that ABCB6 contributes to ADR efflux from leukemia cells, thereby reducing intracellular drug accumulation and weakening its cytotoxic activity. Together, these findings establish ABCB6 as a previously unrecognized efflux transporter that contributes to MDR in leukemia and highlight ABCB6 as a potential therapeutic target for overcoming MDR.