Wnt/-catenin inhibition reverses multidrug resistance in pediatric acute lymphoblastic leukemia

Although 80% of newly diagnosed pediatric patients with acute lymphoblastic leukemia (ALL) become disease-free following appropriate treatment, relapses frequently occur, with dismal prognosis. Therefore, it is urgent to develop novel therapeutic modalities. Resistance to chemotherapy is a major obstacle for the treatment of relapsed ALL. It has been indicated that Wnt pathway is potentially associated with leukemia recurrence. In the current study, a vincristine (VCR)-resistant variant of the human ALL cell line BALL-1 (BALL-1/VCR) that also had relatively specific resistance to both doxorubicin and etoposide was generated. Over-activation of the Wnt/-catenin signaling pathway was observed in BALL-1/VCR cells, whereas Dickkopf-related protein 1 selectively suppressed the Wnt signaling pathway and sensitized the response of BALL-1/VCR to anticancer agents. In addition, prednisolone exposure in combination with Wnt inhibition restored chemo-sensitivity in relapsed ALL blasts. Since the resistance of BALL-1/VCR cells is potentially attributed to the overexpression of MDR-associated protein 1 (MRP1), the development of drug resistance in relapsed ALL may associated with the overexpression of MRP1 and P-glycoprotein. The results of this study demonstrated that, as a potential candidate to mimic relapsed ALL, BALL-1/VCR could be used in further research, while Wnt-inhibition may become a promising therapeutic approach for treating ALL.