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The Role of Breast Cancer Resistance Protein in Acute Lymphoblastic Leukemia

Divisions of Pediatric Oncology and Hematology [S. L. A. P., E. S. J. M. d. B., W. A. K.], Hematology [D. M. v. d. K., E. V.], and Medical Oncology [E. G. E. d. V.], University Hospital Groningen, Groningen 9713 GZ, the Netherlands; Division of Pathology, Free University Medical Center, Amsterdam, the Netherlands [G. L. S., R. J. S.]; and National Cancer Institute, Medicine Branch, NIH, Bethesda, Maryland 20892 [S. E. B.]

ABSTRACT

Purpose: Overexpression of the transporter ABCG2, also known as breast cancer resistance protein and mitoxantrone resistance protein, can confer resistance to a variety of cytostatic drugs, such as mitoxantrone, topotecan, doxorubicin, and daunorubicin. This study analyzes the ABCG2 expression and activity in 46 human de novo acute lymphoblastic leukemia B- and T-lineage (ALL) samples.

Experimental Design: ABCG2 expression was measured flow cytometrically with the BXP-34 monoclonal antibody. ABCG2 functional activity was determined flow cytometrically by measuring mitoxantrone accumulation in combination with the ABCG2 inhibitor fumitremorgin C (FTC). To determine a possible effect of the transporters P-glycoprotein and multidrug resistance-associated protein (MRP1 and MRP2) on mitoxantrone accumulation, the accumulation was investigated in the presence of the P-glycoprotein inhibitor PSC 833 and MRP inhibitor MK-571. The ABCG2 gene was sequenced to investigate the amino acid at position 482.

Results: In B-lineage ALL (n = 23), the median BXP-34:IgG1 ratio was higher, namely 2.4 (range, 1.7–3.7), than in T-lineage ALL (n = 23; 1.9; range, 1.2–6.6; P = 0.003). The addition of FTC to mitoxantrone treatment caused a median increase in mitoxantrone accumulation of 21% (range, 0–140%) in B-lineage ALL. In T-lineage ALL, this FTC effect was less pronounced (5%; range, 0–256%; P = 0.013). The influence of FTC on mitoxantrone accumulation correlated with ABCG2 protein expression (r = 0.52; P < 0.001; n = 43). The increase in mitoxantrone accumulation, when FTC was added to cells treated with both PSC 833 and MK-571, correlated with the ABCG2 expression in B-lineage ALL but not in T-lineage ALL. Sequencing the ABCG2 gene revealed no ABCG2 mutation at position 482 in patients who accumulated more rhodamine after FTC.

Conclusions: This study shows that ABCG2 is expressed higher and functionally more active in B-lineage than in T-lineage ALL.

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