High Expression of Multidrug Resistance-Associated Proteins Predicts Prognosis in Acute Lymphoblastic Leukemia in Children and Adults.

Background: Patients with acute lymphoblastic leukemia (ALL) are treated with different chemotherapeutic drugs, which can be transported by ABC-transporters, including six multidrug resistance-associated proteins (MRPs). New insights suggest that a drug resistance profile, in which multiple transporters act in concert, is more likely to predict prognosis than one single transporter. The aim of this study was to investigate the expression profile of MRP1-6 in ALL in both children and adults and determine its impact on prognosis.

Methods: mRNA expression of MRP1-6 was analyzed by real-time PCR in human de novo ALL samples from 56 children and 49 adults. Of these patients, 32 showed a T-lineage and 73 a B-lineage immunophenotype.

Results: Adults showed a significantly higher expression of MRP1 (median value 1.08 vs. 0.69), MRP2 (0.96 vs. 0.53) and MRP3 (0.31 vs. 0.07) than children. However, no difference in expression levels was observed between children and adults who developed a relapse. High expression of one MRP in individual patients was correlated with increased expression of multiple MRPs. The ability to discriminate between patients who will remain in continuous complete remission and patients who will relapse was determined by receiver operating characteristic (ROC) curves. When children and adults were analyzed together, the area under the ROC curves showed that MRP1 (AUC 0.72, p=0.002), MRP2 (AUC 0.71, p=0.002), MRP3 (AUC 0.72, p=0.001), MRP5 (AUC=0.70, p=0.004) and MRP6 (AUC=0.68, p=0.009) predicted relapse. Using median values as cutoff for high versus low expression, high expression of all six MRP genes, except MRP4, was significantly associated with reduced event-free survival in children and adults (Kaplan-Meier curves with Log-rank tests).

Conclusion: Our results suggest that a profile with high mRNA expression of MRP1, MRP2, MRP3, MRP5 and MRP6 is involved in drug resistance in ALL. This unfavorable profile is more often observed in adults, and is associated with reduced event-free survival.