Ephrin type-B receptor 4 is an essential mediator in drug-resistance of acute myeloid leukemia cells to Adriamycin.

Objective: Ephrin type-B receptor 4 (EphB4) plays an important role in human carcinogenesis. This study investigated the effects of EphB4 expression in drug-resistance of acute myeloid leukemia cells to Adriamycin using myeloid leukemia cell lines with different degrees of differentiation, including an Adriamycin-resistant HL60 cell line as a model. The data showed that the EphB4 protein was differentially expressed in these myeloid leukemia cell lines, which expression was associated with sensitivity of myeloid leukemia cells to Adriamycin treatment in vitro. Furthermore, EphB4 protein stimulated by EphrinB2-Fc sensitized HL60/ADM cells to Adriamycin in a dose-dependent manner. Specifically, pre-incubation of HL60/ADM with 4 µg/ml EphrinB2-Fc protein for 30 min significantly sensitized tumor cell to Adriamycin treatment by reduction of tumor cell viability and induction of apoptosis (p<0.001), while there was no significant change in other groups (p>0.05). These data provided a proof-of-principle for further development of the EphB4-based strategy for treatment of drug-resistant leukemia.