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The Role of Breast Cancer Resistance Protein in Acute Lymphoblastic Leukemia

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The Role of Breast Cancer Resistance Protein in Acute Lymphoblastic Leukemia Vol. 9, 5171–5177, November 1, 2003 Clinical Cancer Research 5171 Featured Article The Role of Breast Cancer Resistance Protein in Acute Lymphoblastic Leukemia Sabine L. A. Plasschaert, 0.013). The influence of FTC on mitoxantrone accumulation > P ;0.52 ؍ Dorina M. van der Kolk, Eveline S. J. M. de Bont, correlated with ABCG2 protein expression (r ؍ Willem A. Kamps, Kuniaki Morisaki, 0.001; n 43). The increase in mitoxantrone accumulation, when FTC was added to cells treated with both PSC 833 and Susan E. Bates, George L. Scheffer, MK-571, correlated with the ABCG2 expression in B-lineage Rik J. Scheper, Edo Vellenga, and ALL but not in T-lineage ALL. Sequencing the ABCG2 gene Elisabeth G. E. de Vries1 revealed no ABCG2 mutation at position 482 in patients who Divisions of Pediatric Oncology and Hematology [S. L. A. P., accumulated more rhodamine after FTC. E. S. J. M. d. B., W. A. K.], Hematology [D. M. v. d. K., E. V.], and Conclusions: This study shows that ABCG2 is ex- Medical Oncology [E. G. E. d. V.], University Hospital Groningen, pressed higher and functionally more active in B-lineage Groningen 9713 GZ, the Netherlands; Division of Pathology, Free than in T-lineage ALL. 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.] Introduction The prognosis of ALL2 has improved over the last decades, in children even more than in adults. Still, many ALL patients Abstract do not achieve a complete remission or develop a relapse (1, 2). Purpose: Overexpression of the transporter ABCG2, Resistance to chemotherapeutic agents plays an important role. also known as breast cancer resistance protein and mitox- MDR is defined as resistance to multiple, structurally and func- antrone resistance protein, can confer resistance to a variety tionally unrelated natural product drugs. One mechanism of of cytostatic drugs, such as mitoxantrone, topotecan, doxo- MDR is the overexpression of members of the ABC superfamily rubicin, and daunorubicin. This study analyzes the ABCG2 of membrane transporters. This family of transporters consists expression and activity in 46 human de novo acute lympho- of a number of proteins, including P-gp and the MRPs (MRP1 blastic leukemia B- and T-lineage (ALL) samples. and MRP2). Contradictory results have been observed with Experimental Design: ABCG2 expression was measured respect to the prognostic impact of P-gp expression and func- flow cytometrically with the BXP-34 monoclonal antibody. tional activity (3–8). For MRP1 protein and mRNA expression, ABCG2 functional activity was determined flow cytometri- neither a difference has been found between initial and relapse cally by measuring mitoxantrone accumulation in combina- samples, nor a correlation with complete response or survival tion with the ABCG2 inhibitor fumitremorgin C (FTC). To (3). We have studied previously the functional activity of MRP1 determine a possible effect of the transporters P-glycopro- and MRP2 in children and adults with ALL, and observed no tein and multidrug resistance-associated protein (MRP1 and correlation between functional activity and clinical outcome (9). MRP2) on mitoxantrone accumulation, the accumulation Another ATP-binding cassette transporter has been identi- was investigated in the presence of the P-glycoprotein inhib- fied in a MDR human breast cancer cell line MCF-7/AdrVp (10, itor PSC 833 and MRP inhibitor MK-571. The ABCG2 gene 11). This cell line shows an ATP-dependent reduction in the was sequenced to investigate the amino acid at position 482. intracellular accumulation of anthracycline anticancer drugs, in ؍ Results: In B-lineage ALL (n 23), the median BXP- the absence of overexpression of known MDR transporters such 34:IgG1 ratio was higher, namely 2.4 (range, 1.7–3.7), than as P-gp or MRP. This transporter protein was named ABCG2, ؍ ؍ in T-lineage ALL (n 23; 1.9; range, 1.2–6.6; P 0.003). and is also known as breast cancer resistance protein, placental The addition of FTC to mitoxantrone treatment caused a ABC transporter, or mitoxantrone resistance protein. Several median increase in mitoxantrone accumulation of 21% human cancer cell lines selected for resistance to mitoxantrone (range, 0–140%) in B-lineage ALL. In T-lineage ALL, this or topotecan have shown a marked ABCG2 overexpression. In ؍ FTC effect was less pronounced (5%; range, 0–256%; P addition, enforced expression of the full-length ABCG2 cDNA in MCF-7 breast cancer cells confers resistance to mitoxantrone, bisantrene, topotecan, and doxorubicin or daunorubicin in the presence of verapamil (11–14). The physiological function of Received 2/7/03; revised 6/25/03; accepted 7/2/03. ABCG2 may be similar to P-gp, because it is also located in the The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. This work was supported by a grant of the Foundation of Pediatric 2 The abbreviations used are: ALL acute lymphoblastic leukemia; MDR, Oncology Groningen (SKOG 99–01). multidrug resistance; MRP, multidrug-resistant protein; P-gp, P-glyco- 1 To whom requests for reprints should be addressed, at Department of protein; FTC, fumitremorgin C; AML, acute myelogenous leukemia; Internal Medicine, Division of Medical Oncology, University Hospital FACS, fluorescence-activated cell sorter; PE, phycoerythrin; MFI, me- Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands. Phone: dian fluorescence intensity; Rh123, rhodamine 123; CF, carboxyfluo- 31-503612821; Fax: 31-503614862; E-mail: [email protected]. rescein. Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2003 American Association for Cancer Research. 5172 ABCG2 Expression and Activity in ALL blood-brain barrier, the placenta, the liver, and intestinal tract sone, daunorubicin, doxorubicin, methotrexate, and vincristine. (15). The spectrum of ABCG2 substrates shows an overlap with The adult patients received a regimen including the MDR drugs that of P-gp and MRP. All three of the transporters can extrude prednisone, doxorubicin, vincristine, methotrexate, and etopo- the anthracyclines, such as daunorubicin, doxorubicin, and epi- side (26). rubicin. P-gp (16), ABCG2, and probably MRP1 (17, 18) can Mononuclear cells from bone marrow or peripheral blood also transport mitoxantrone. There are indications that the spec- were isolated on a Ficoll-Isopaque (Nycomed, Oslo, Norway) trum of drugs transported by ABCG2 might differ in cell lines density gradient by centrifugation for 20 min at 800 ϫ g. The because of a mutation in the ABCG2 gene at amino acid cells were cryopreserved in RPMI 1640 supplemented with 10% position 482 (19). When a mutation is present in the ABCG2 FCS and 10% DMSO (Merck, Amsterdam, the Netherlands) and gene with threonine or glycine situated at position 482 instead of stored at Ϫ196°C. Upon analysis cells were thawed, centrifuged arginine, ABCG2 is able to transport rhodamine and doxorubi- in newborn calf serum (Life Technologies, Inc., Breda, the cin additionally (19) but not methotrexate (20). Netherlands), treated with DNase (Boehringer Mannheim, Mitoxantrone, methotrexate, daunorubicin, and doxorubi- Mannheim, Germany), and washed with RPMI 1640. Immuno- cin are used frequently during the induction or consolidation phenotyping showed that all of the samples contained Ͼ90% of 6 phase in ALL, indicating that ABCG2 might have clinical leukemic cells. For immunophenotyping, 0.5 ϫ 10 cells were impact in this patient group. The present study demonstrates that incubated with 5 ␮l of FITC- or phycoerythrin-labeled mouse the ABCG2 protein is expressed in ALL. The functional activity monoclonal antibodies to CD117, CD3, CD7 (all IQ Products, was measured by mitoxantrone accumulation in the absence or Groningen, the Netherlands), CD2, CD10, CD19, CD20, CD33, presence of the ABCG2 inhibitor FTC (21), and FTC in com- CD34, or IgG isotype-matched controls (all Becton Dickinson, bination with the inhibitors of the other transporters P-gp and Woerden, the Netherlands) for 30 min at 4°C. Subsequently, MRP1, which might obscure the ABCG2 function (12, 22). The cells were washed with RPMI 1640 and analyzed with a FAC- ABCG2 gene was sequenced in patients who accumulated more Star flow cytometer (Becton Dickinson Medical Systems, Sha- rhodamine after FTC, to investigate the amino acid at position ron, MA). The immature markers CD34 and CD117, expressed 482. Because ABCG2 expression is correlated with an immature only on progenitor cells, were analyzed in both B-lineage and phenotype in normal human hematopoietic cells (15, 23, 24) and T-lineage ALL. For B-lineage ALL samples, the B-lineage AML blasts (21), we also determined the immunophenotype of markers CD10, CD19, and CD20 were used. The T-lineage the patient samples. markers CD3 and CD7 were investigated in T-lineage ALL samples. Because the myeloid marker CD33 correlated with P-gp functional activity in an earlier study (9), CD33 expression Materials and Methods was also measured. Cell Lines. The drug-sensitive human breast cancer cell Flow Cytometric Detection of ABCG2 Protein Expres- line MCF-7 and its mitoxantrone-resistant counterpart MCF-7 sion. ABCG2 protein expression was measured with the MR, which overexpresses ABCG2 but not P-gp or MRP-1, were monoclonal antibody BXP-34 (27), which recognizes an internal cultured in RPMI 1640 (Bio Whittaker, Brussels, Belgium) epitope of the ABCG2 protein. Cells (0.5 ϫ 106) were incubated supplemented with 10% FCS (Hyclone, Logan, UT). The with FACS lysing solution (Becton Dickinson) to permeabilize MCF-7 MR cell line was cultured in the presence of 80 nM the cell membranes for 10 min at room temperature. Then the mitoxantrone. The human small cell lung cancer cell line GLC4, cells were incubated for 15 min at room temperature, with 1% the in vitro doxorubicin-selected MRP1-overexpressing subline goat serum in PBS [PBS: 140 mM NaCl, 9.0 mM GLC4/ADR, and the MDR-1 transfected cell line GLC4/P-gp Na2HPO42H2O, and 1.3 mM NaH2PO42H2O (pH 7.4)] contain- were also cultured in RPMI 1640 with 10% FCS.
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