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Blood, 15 May 2002, Vol. 99, No. 10, pp. 3763-3770
NEOPLASIA
Expression and activity of breast cancer resistance protein
(BCRP) in de novo and relapsed acute myeloid leukemia
Dorina M. van der Kolk,
Edo Vellenga,
George L. Scheffer,
Michael Müller,
Susan E. Bates,
Rik J. Scheper, and
Elisabeth G. E. de Vries
From the Divisions of Hematology and Medical Oncology,
University Hospital Groningen, The Netherlands; Department of
Pathology, Free University Medical Center, Amsterdam, The Netherlands;
Division of Nutrition, Metabolism, and Genomics, University Wageningen,
The Netherlands; and National Cancer Institute, Medicine Branch,
National Institutes of Health, Bethesda, MD.
Overexpression of the breast cancer resistance protein (BCRP)
efflux pump in human cancer cell lines results in resistance to a
variety of cytostatic agents. The aim of this study was to analyze BCRP
protein expression and activity in acute myeloid leukemia (AML) samples
and to determine whether it is up-regulated due to clonal selection at
relapse/refractory disease. BCRP protein expression was measured flow
cytometrically with the monoclonal antibodies BXP-34 and BXP-21 in 20 paired samples of de novo and relapsed/refractory AML.
BXP-34/immunoglobulin G1 ratios were observed of 1.6 ± 0.5 (mean
± SD, range 0.8-2.7) and BXP-21/immunoglobulin G2a ratios of
4.9 ± 3.0 (range 1.1-14.5) in the patient samples versus
9.8 ± 6.8 and 6.5 ± 2.4, respectively, in the MCF-7 cell line.
BCRP activity was determined flow cytometrically by measuring mitoxantrone accumulation in absence and presence of the inhibitor fumitremorgin C. Mitoxantrone accumulation, expressed as mean fluorescence intensity (MFI), varied between 44 and 761 MFI
(227 ± 146 MFI) and correlated inversely with BCRP expression
(r =  0.58, P < .001). Addition of
fumitremorgin C showed a small increase in mitoxantrone accumulation
(11 ± 29 MFI, n = 40) apart from the effect of PSC833 and MK-571.
No consistent up-regulation of BCRP expression or activity was observed
at relapse/refractory disease; some cases showed an increase and other
cases a decrease at relapse. Relatively high BCRP expression correlated
with immature immunophenotype, as determined by expression of the
surface marker CD34 (r = 0.54, P = .001).
In conclusion, this study shows that BCRP protein is expressed at low
but variable levels in AML, especially in immature CD34+
cells. BCRP was not consistently up-regulated in relapsed/refractory AML.
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