Impact Of WAVE1 On MDR1,MRP1,BCRP In Children With Acute Lymphoblastic Leukemia

Background: Chemotherapy is one of the main treaments for children with acute leukemia (AL). Multidrug resistance (MDR) is an important reason of treatment failure in children with acute leukemia, especially in acute nonlymphoblastic leukemia (ANLL). The occurrence of multidrug resistance strongly decreases the long-term event-free survival rate.In previous researches, we have confirmed that cytoskeletal regulatory protein WASP-family verprolin homologous protein 1(WAVE1) is involved in the pathogenesis of children with acute lymphoblastic leukemia (ALL), and with positive impact. At the active stage (in patients with primary and recurrent), the expression of WAVE1 continued to increase, while back to normal levels at complete remission stage. WAVE1 was also found involved in MDR. It can be a new way to reverse multidrug resistance if we can confirm WAVE1's impact to multidrug resistance genes.Objective: To investigate WAVE1's impact to the expression and regulation of multidrug resistance gene 1, multidrug resistance-associated protein gene 1, and breast cancer resistance protein gene.Methods: WAVE1, MDR1, MRP1, BCRP mRNA expression in bone marrow mononuclear cells (BMMCs) were tested by Real-time fluorescence quantitative PCR (RQ-PCR) in a cohort of fifty-two children with acute myeloblastic leukemia. K562 cell was transient-transfected by PCDNA3. 1A-WAVE1 reconstructed plasmid and the expression of WAVE1, MDR1, MRP1 and BCRP before and after transfection were investigated by real-time PCR.Results: Twenty-one patients were refractory or relapsed during the follow-up and thirty-one patients were found in continuous remission. Levels of WAVE1, MDR1, MRP1, BCRP's expression in refractory/relapsing group were much higher than in complete continuous remission (CCR) group (P<0.05). Compared with continuous remission group we showed that higher expression of WAVE1 mRNA in newly diagnosed or relapsed ANLL children's BMMCs (P<0.05).WAVE1 and MDR1 mRNA expression in K562/A02 was much higher than that in K562.Levels of WAVE1, MDR1, MRP1, BCRP mRNA expression were increased to varying degrees after transfecting pCDNA3. 1A-WAVE1 reconstructed plasmid in K562 cells.Conclusion: Our results suggested that higher levels of WAVE1 in BM indicates an unfavorable prognosis in children with ANLL. WAVE1 is involved in the MDR mechanisms and regulates the level of MRP1 and BCRP expression.