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

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.