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Expression of Multidrug Resistance–Associated Proteins Predicts Prognosis in Childhood and Adult Acute Lymphoblastic Leukemia

Authors' Affiliations: Departments of ¹ Pediatric Oncology and Hematology, ² Epidemiology, ³ Hematology, ⁴ Gastroenterology and Hepatology, and ⁵ Medical Oncology, University Medical Center Groningen, Groningen, the Netherlands

Requests for reprints: Edo Vellenga, Division of Hematology, Department of Internal Medicine, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands. Phone: 31-50-3612354; Fax: 31-50-3614862; E-mail: E.Vellenga{at}int.umcg.nl.

Purpose: Patients with acute lymphoblastic leukemia (ALL) are treated with a variety of chemotherapeutic drugs, which can be transported by six multidrug resistance–associated proteins (MRP). These MRPs have strongly overlapping functional activities. The aim of this study was to investigate the expression levels of MRP1 to MRP6 and study their effect on prognosis.

Experimental Design: The mRNA expression levels of MRP1 to MRP6 were analyzed by quantitative real-time PCR in leukemic blasts of 105 de novo ALL patients (adults, n = 49; children, n = 56) including 70% B-lineage and 30% T-lineage ALL patients.

Results: Adults showed a higher expressions of MRP1 (P = 0.008), MRP2 (P = 0.026), and MRP3 (P = 0.039) than children. Interestingly, this difference disappeared when patients were categorized based on clinical outcome. Relapsed patients showed a higher expression of all MRP genes, except MRP4. For the total group of ALL patients, the expressions of MRP1, MRP2, MRP3, MRP5, and MRP6 predicted relapse. Moreover, high expression of all MRP genes, except MRP4, was associated with a reduced relapse-free survival in children and adults (MRP1, P = 0.005; MRP2, P = 0.008; MRP3, P = 0.001; MRP5, P = 0.016; MRP6, P = 0.037).

Conclusions: The present study shows that a subset of ALL patients with high MRP expression has an unfavorable prognosis independently of age.

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