title: The multidrug resistance-associated protein 3 (MRP3) is associated with a poor outcome in childhood ALL and may account for the worse prognosis in male patients and T-cell immunophenotype.
abstract: The family of multidrug resistance-associated proteins (MRPs) belongs to the superfamily of adenosine triphosphate-binding-cassette (ABC) transporters, which have the ability to function as outward pumps for chemotherapeutic drugs and therefore might be involved in drug resistance. In this study the expression of the MRP2, MRP3, MRP4, MRP5, and SMRP genes was measured using TaqMan real-time polymerase chain reaction (PCR) in 103 children with previously untreated acute lymphoblastic leukemia (ALL) (precursor B-cell ALL [B-ALL], n = 71; T-cell ALL [T-ALL], n = 32). All 5 genes were expressed with a great variability. Only MRP3 expression was associated with a significantly worse prognosis (P =.008). The median expression of MRP3 was 10-fold higher in T-ALL than in precursor B-ALL (P <.001) and 4-fold higher in male patients than in female patients (P <.001). The prognostic impact of MRP3 was independent of immunophenotype or sex. Higher levels of MRP3 were found in patients with a poor in vivo response to prednisone, but this could not be confirmed in an independent case-control study (40 patients) for prednisone response. In healthy donors, the median expression of MRP4 was 4-fold higher in bone marrow and 8-fold higher in CD34+ stem cells compared with peripheral blood (P =.002). Our results suggest that MRP3 is involved in drug resistance in childhood ALL. It therefore represents an interesting target to overcome multidrug resistance. High levels of MRP3 could possibly be the reason for the poorer prognosis of male patients or patients who have T-ALL. Similar to other members of the family of ABC transporters, MRP4 seems to be a marker for immature stem cells.
authors.affiliation: Klinikum der FSU Jena, Klinik für Kinder-und Jugendmedizin, Postfach, 07740 Jena, Germany. daniel@steinba.ch
authors.forename: Daniel
authors.initials: D
authors.lastname: Steinbach
authors.forename: Susann
authors.initials: S
authors.lastname: Wittig
authors.forename: Gunnar
authors.initials: G
authors.lastname: Cario
authors.forename: Susanne
authors.initials: S
authors.lastname: Viehmann
authors.forename: Angelika
authors.initials: A
authors.lastname: Mueller
authors.forename: Bernd
authors.initials: B
authors.lastname: Gruhn
authors.forename: Ralf
authors.initials: R
authors.lastname: Haefer
authors.forename: Felix
authors.initials: F
authors.lastname: Zintl
authors.forename: Axel
authors.initials: A
authors.lastname: Sauerbrey
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000097:blood* / Q000188:drug therapy / Q000401:mortality; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000097:blood* / Q000235:genetics; D009363:Neoplasm Proteins / Q000097:blood* / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood* / Q000188:drug therapy / Q000401:mortality; D011379:Prognosis; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000097:blood; D012334:RNA, Neoplasm / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C114462:multidrug resistance-associated protein 3