Deletion of the multidrug resistance protein MRP1 gene in acute myeloid leukemia: the impact on MRP activity

Deletion of the multidrug resistance gene MRP1 has been demonstrated in acu te myeloid leukemia (AML) patients with inversion of chromosome 16 (inv[16] ), These AML patients are known to have a relatively favorable prognosis, w hich suggests that MRP1 might play an important role In determining clinica l outcome. This study analyzed MRP1 deletion by fluorescent in situ hybridi zation (FISH), with a focus on inv(16) AML patients. Functional activity of multidrug resistance protein (MRP) was studied in a flow cytometric essay 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 obse rved. 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); thi s 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 m RNA was detected in patients with 1 or 2 MRP1 FISH signals, but not in pati ents 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 M RP2 and MRP6 mRNA was observed. In conclusion, this study shows that MRP ac tivity varies among inv(16) AML cases and does not differ from that in norm al hematopoietic cells; this might be in part due to the up-regulation of o ther MRP genes.(Blood. 2000;95:3514-3519) (C) 2000 by The American Society of Hematology.