Response to chemotherapy and expression of the genes encoding the multidrug resistance-associated proteins MRP2, MRP3, MRP4, MRP5, and SMRP in childhood acute myeloid leukemia.
OBJECTIVE
The family of multidrug resistance-associated proteins (MRPs) belongs to the ATP-binding cassette superfamily of transporters, which have the ability to function as outward pumps for chemotherapeutic drugs. Their structure, function, and substrate specificity have been studied intensively, but little is known about their clinical relevance in malignant diseases.


METHODS
In this study, the expression of the MRP2, MRP3, MRP4, MRP5, and SMRP genes was measured using TaqMan real-time PCR in 53 children with de novo acute myeloid leukemia. Nine patients were also analyzed in relapse.


RESULTS
MRP3 gene expression was higher in patients who did not achieve remission (P = 0.023). Expression of MRP2 (P = 0.09) or MRP3 (P = 0.041) was associated with a lower rate of survival, and patients who expressed high levels of both genes had a particularly poor prognosis (P < 0.01). No significant association was found for overall survival or remission rate and the expression of MRP4, MRP5, and SMRP.


CONCLUSIONS
This study provides first data on the clinical relevance of five MRPs in acute myeloid leukemia patients. The results strongly suggest that MRP3 and possibly also MRP2 are involved in drug resistance in this disease. Those two proteins therefore represent interesting markers for risk-adapted therapy and possible targets for the development of specific drugs to overcome multidrug resistance.
Steinbach
Daniel
D
University Children's Hospital, 07740 Jena, Germany. daniel@steinba.ch
Lengemann
Janka
J
Voigt
Astrid
A
Hermann
Johann
J
Zintl
Felix
F
Sauerbrey
Axel
A
D000293:Adolescent; D014408:Biomarkers, Tumor; D002648:Child; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000401:mortality / Q000628:therapy*; D008297:Male; D024101:Mitochondrial Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis*; D012008:Recurrence; D012074:Remission Induction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012269:Ribosomal Proteins / Q000096:biosynthesis*; D029701:Saccharomyces cerevisiae Proteins; D013997:Time Factors; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D024101:Mitochondrial Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; C073492:ABCC4 protein, human; C120809:ABCC5 protein, human; C093947:MRP2 protein, S cerevisiae; C114462:multidrug resistance-associated protein 3