EphB4/ephrinB2 Contributes to Imatinib Resistance in Chronic Myeloid Leukemia Involved in Cytoskeletal Proteins.

ABSTRACT

INTRODUCTION: The mechanism of EphB4/ephrinB2 in the resistance of chronic myelogenous leukemia to imatinib keeps unknown. METHODS: The imatinib resistant chronic myelogenous leukemia cell line-K562-R, was established. EphB4 receptor expression was detected in patients and resistant cells. Cell migration and drug sensitivity were tested in the EphB4 knockdown cells and mouse models. RESULTS: The EphB4 receptor was over-expressed in blast crisis patients compared to chronic phase patients. The level of EphB4 receptor expression was associated with a complete cytogenetic response within 12 months. Enhanced expression of the EphB4 receptor was detected in the K562-R cells. EphB4 knockdown inhibited cell migration ability and restored sensitivity to imatinib in vitro and in vivo. Restored sensitivity to imatinib was observed in K562-R cells, along with increased levels of phospho-EphB4 and decreased phosphorylation levels of RhoA, Rac1, and Cdc42. CONCLUSION: Our study illustrates that aberrant activation of EphB4/ephrinB2 may mediate chronic myeloid leukemia resistance involved in cytoskeletal proteins.