Blood, Vol. 95 No. 11 (June 1), 2000:
pp. 3514-3519
Deletion of the multidrug resistance protein MRP1 gene in
acute myeloid leukemia: the impact on MRP activity
Dorina M. van der Kolk,
Edo Vellenga,
Anneke Y. van der Veen,
Leonore Noordhoek,
Hetty Timmer-Bosscha,
Gert J. Ossenkoppele,
Reinier A. Raymakers,
Michael Müller,
Eva van den Berg, and
Elisabeth G. E. de Vries
From the Divisions of Hematology, Medical Oncology, and
Gastroenterology and Hepatology, University Hospital of Groningen,
Department of Medical Genetics, University of Groningen; Division of
Hematology, Free University Hospital Amsterdam; Division of Hematology,
University Hospital Nijmegen, The Netherlands.
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.
