title: Deletion of the multidrug resistance protein MRP1 gene in acute myeloid leukemia: the impact on MRP activity.
abstract: Deletion of the multidrug resistance gene MRP1 has been demonstrated in acute myeloid leukemia (AML) patients with inversion of chromosome 16 (inv[16]). These AML patients are known to have a relatively favorable prognosis, which suggests that MRP1 might play an important role in determining clinical outcome. This study analyzed MRP1 deletion by fluorescent in situ hybridization (FISH), with a focus on inv(16) AML patients. Functional activity of multidrug resistance protein (MRP) was studied in a flow cytometric assay with the use of the MRP substrate carboxyfluorescein (CF) and the inhibitor MK-571. MRP1, MRP2, and MRP6 messenger RNA (mRNA) expression was determined with reverse transcriptase-polymerase chain reaction (RT-PCR). The results were compared with normal bone marrow cells. MRP1 deletion was detected in 7 AML patients; 2 cases showed no MRP1 FISH signals, and 5 cases had 1 MRP1 signal, whereas in 4 AML patients with inv(16) no MRP1 deletions were observed. A variability in MRP activity, expressed as CF efflux-blocking by MK-571, was observed (efflux-blocking factors varied between 1.2 and 3.6); this correlated with the number of MRP1 genes (r = 0.91, P <. 01). MRP activity in the AML cases was not different from normal hematopoietic cells. MRP1 mRNA was detected in patients with 1 or 2 MRP1 FISH signals, but not in patients with no MRP1 signals. MRP2 and MRP6 mRNA were expressed predominantly in AML samples with 1 MRP1 signal, whereas in normal bone marrow cells no MRP2 and MRP6 mRNA was observed. In conclusion, this study shows that MRP activity varies among inv(16) AML cases and does not differ from that in normal hematopoietic cells; this might be in part due to the up-regulation of other MRP genes.
authors.affiliation: Divisions of Hematology, Medical Oncology, and Gastroenterology and Hepatology, University Hospital of Groningen, Department of Medical Genetics, University of Groningen, Groningen, The Netherlands.
authors.forename: D M
authors.initials: DM
authors.lastname: van Der Kolk
authors.forename: E
authors.initials: E
authors.lastname: Vellenga
authors.forename: A Y
authors.initials: AY
authors.lastname: van Der Veen
authors.forename: L
authors.initials: L
authors.lastname: Noordhoek
authors.forename: H
authors.initials: H
authors.lastname: Timmer-Bosscha
authors.forename: G J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.forename: R A
authors.initials: RA
authors.lastname: Raymakers
authors.forename: M
authors.initials: M
authors.lastname: Müller
authors.forename: E
authors.initials: E
authors.lastname: van Den Berg
authors.forename: E G
authors.initials: EG
authors.lastname: de Vries
mesh_terms: D000208:Acute Disease; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D020137:Base Pair Mismatch; D001854:Bone Marrow Cells / Q000166:cytology / Q000473:pathology; D018288:Carcinoma, Small Cell; D002478:Cells, Cultured; D007446:Chromosome Inversion; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity; D018432:Drug Resistance, Multiple / Q000235:genetics*; D017353:Gene Deletion; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008175:Lung Neoplasms; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D004317:Doxorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein; C078444:MSH3 protein, human; C421109:multidrug resistance-associated protein 1