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Intracellular ABC Transporter A3 Confers Multidrug Resistance in Leukemia Cells by Lysosomal Drug Sequestration

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Intracellular ABC Transporter A3 Confers Multidrug Resistance in Leukemia Cells by Lysosomal Drug Sequestration Leukemia (2008) 22, 1576–1586 & 2008 Macmillan Publishers Limited All rights reserved 0887-6924/08 $30.00 www.nature.com/leu ORIGINAL ARTICLE Intracellular ABC transporter A3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration B Chapuy1, R Koch1, U Radunski1, S Corsham1, N Cheong2, N Inagaki3, N Ban4, D Wenzel5, D Reinhardt6, A Zapf7, S Schweyer8, F Kosari9, W Klapper9, L Truemper1 and GG Wulf1 1Department of Hematology and Oncology, Georg-August-University Goettingen, Goettingen, Germany; 2Department of Physiology, University of Pennsylvania, Philadelphia, PA, USA; 3Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 4Department of Physiology, Akita University School of Medicine, Akita, Japan; 5Department of Neurobiology, Max Planck Institute for Biophysical Chemistry, Goettingen, Germany; 6Department of Pediatrics, Medizinische Hochschule Hannover, Hannover, Germany; 7Department of Medical Statistics, Georg-August-University Goettingen, Goettingen, Germany; 8Department of Pathology, Georg-August-University Goettingen, Goettingen, Germany and 9Department of Hematopathology and Lymph Node Registry, University of Schleswig- Holstein, Kiel, Germany Multidrug resistance (MDR) seriously limits the efficacy of cells exhibiting progenitor cell properties both in vitro and chemotherapy in patients with cancer and leukemia. Active in vivo in numerous other types of cancer.7 As for the transport across membranes is essential for such cellular drug resistance, largely provided by ATP-binding cassette (ABC) mechanism of dye and drug exclusion, we first discovered the transport proteins. Intracellular drug sequestration contributes overexpression of the ATP-binding cassette transporter A3 to MDR; however, a genuine intracellular ABC transport protein (ABCA3) in leukemic SP cells in an in-vivo leukemia model. with MDR function has not yet been identified. Analyzing the Those data were confirmed in series of malignant SP cells from intrinsic drug efflux capacity of leukemic stem cells, we found both patients with neuroblastoma and AML.7–9 Here we the ABC transporter A3 (ABCA3) to be expressed consistently demonstrate that ABCA3 was expressed in virtually all cases in acute myeloid leukemia (AML) samples. Greater expression of ABCA3 is associated with unfavorable treatment outcome, of AML from a series of 119 pediatric and adult patients, and and in vitro, elevated expression induces resistance toward a that high levels of expression are associated with a significantly broad spectrum of cytostatic agents. ABCA3 remains localized impaired prognosis. We discovered that expression of ABCA3 within the limiting membranes of lysosomes and multivesicular induces a phenotype of broad multidrug resistance (MDR), bodies, in which cytostatics are efficiently sequestered. In mediated by subcellular drug sequestration to lysosomes and addition to AML, we also detected ABCA3 in a panel of finally gathered evidence of ABCA3 expression in all major lymphohematopoietic tissues and transformed cell lines. In conclusion, we identified subcellular drug sequestration types of malignant lymphohematopoietic disease. mediated by the genuinely intracellular ABCA3 as being a clinically relevant mechanism of intrinsic MDR. Leukemia (2008) 22, 1576–1586; doi:10.1038/leu.2008.103; Patients, materials and methods published online 8 May 2008 Keywords: drug resistance; ABCA3; lysosome Patients For the AML cohort of 119 patients, the bone marrow (n ¼ 112) and peripheral blood (n ¼ 7) specimens analyzed in this study represented archival diagnostic material collected from children Introduction treated within the German multicenter BFM98 protocol, and adults treated according to the German HD98A and B protocol Despite many improvements in the efficacy of anticancer at the University Hospital in Goettingen, Germany. The study agents, the resistance of tumor cells to cytostatic drugs remains was submitted to the Ethics Committee of the University of the major cause of treatment failure in patients with dissemi- Goettingen, and no objections were raised. The clinical nated malignant diseases. As a paradigm, multiagent chemo- characteristics of the AML study population are reported in therapy induces complete hematological remission in most Supplemental Table 1. As control samples, adult human bone patients with acute myeloid leukemia (AML), but the majority of marrow progenitor cells were isolated from routine diagnostic such patients still experience relapse and will finally succumb to posterior iliac crest aspirates of individuals without marrow the disease.1 On the cellular level, such leukemic cells initiating disease involvement, again following internal review board (IRB) relapse must combine in one cell the resistance to cytostatic approval. The tissue array of aggressive lymphomas was collected drugs with the capacity for clonal outgrowth.2–4 Applying the from patients participating in the German multicenter studies Hoechst 33342 staining technique to isolate stem cells with side NHLB1, NHLB2 and the Mabthera International Trial of the population (SP) properties,5 we described such a leukemic German high-grade lymphoma study group. Informed consent to progenitor cell with intrinsic drug efflux capacity some years the scientific evaluation of the tissue samples was obtained from ago.6 Consecutively, we and others have detected malignant SP the patients on study inclusion, and permission for this analysis was obtained from the IRB of the Deutsche Studiengruppe Hochmaligne Non-Hodgkin-Lymphome study group. Correspondence: Professor Dr GG Wulf, Department of Hematology and Oncology, Georg-August-University Goettingen, Robert-Koch-Str 40, Goettingen 37075, Germany. E-mail: [email protected] Reagents, cells, plasmids and antibodies Received 12 February 2008; revised 28 March 2008; accepted 28 The stable ABCA3-eGFP and green fluorescent protein (GFP) March 2008; published online 8 May 2008 transfectants HEK293-ABCA3/eGFP and HEK293-eGFP were Multidrug resistance in leukemia cells B Chapuy et al 1577 obtained from the embryonic kidney cell line HEK293 as 58 1C) and elongation (60 s at 72 1C) followed by a melting curve described previously and were routinely propagated in Dulbecco’s analysis. Subsequently, the threshold PCR cycle number (CT) modified Eagle’s medium supplemented with 300 mg/ml G418. was obtained when the increase in the fluorescence signal of the For cytotoxicity assays, the transfected cell lines were propa- PCR product indicated exponential amplification. This value gated without G418 for four passages, without losing transgene was then normalized to the threshold PCR cycle number expression as evaluated by fluorescence microscopy. The obtained for b-actin mRNA from a parallel sample. The hABCA3 pEGFP-N1-ABCA3 wild-type (wt) and pEGFP-N1-ABCA3 primer (us 50-TTCTTCACCTACATCCCCTAC-30;ds50-CCTTTCG N568D mutant plasmids were described previously.10 The CCTCAAATTTCCC-30) yielded an amplicon of 139 bp, the monoclonal mouse antibody to early endosomal antigen 1 b-actin primer (us 50-CACACTGTGCCCATCTACGA-30;ds50-TGA (EEA1) was obtained commercially (Transduction Laboratories), GGATCTTCATGAGCTAGTCAG-30) and amplicon of 99 bp. the antibodies to lysosomal-associated membrane protein 1 Transcripts of mRNA from the cell line HL60, which displayed (LAMP1, code H4A3) and LAMP2 (code H4B4) were from the weak expression of hABCA3 both on the RNA and protein Developmental Studies Hybridoma Bank (Iowa City, IA, USA). levels, were run in parallel with all reactions, and the values of Human MPR46 was detected using the monoclonal antibody ABCA3 levels were reported using HL60 with the expression (code 10C6), and human ABCA3 with a polyclonal rabbit anti- level of 1 as standard. human ABCA3 antibody.11 The myeloid leukemia cell line HL60 (DSMZ, Braunschweig, Germany) was propagated in RPMI 1640 supplemented with 25 mM 4-(2-hydroxyethyl)-1- Microscopy piperazineethanesulfonic acid, GlutaMAX I (Gibco-BRL, For the routine detection of ABCA3 on sorted cell populations, Karlsruhe, Germany), penicillin/streptomycin (Sigma, Stein- we performed indirect immunocytology following cytocentrifu- heim, Germany and Biochrom, Berlin, Germany) and 10% gation for 10 min at 800 g and fixation with 4% paraformalde- heat-inactivated fetal calf serum (Gibco-BRL). The T-cell hyde (PFA)/phosphate-buffered saline (PBS). The primary lymphoma/leukemia cell lines Jurkat and HUT78 (DSMZ) and antibody to ABCA3, a polyclonal rabbit serum, was diluted the variant PM1 of HUT78, as well as the natural killer (NK) cell 1:200 in PBS and incubated overnight. Cells were fixed in 4% line YT (DSMZ) were also propagated in RPMI 1640 supple- PFA/PBS, followed by blocking of endogenous peroxidase and mented as above. The NK cell line NK92 (kindly provided by T visualized using the horseradish peroxidase reaction with the Tonn, Frankfurt, Germany) was cultured in X-vivo medium Envision system according to the manufacturer’s instructions (BioWhittaker, Taufkirchen, Germany), containing 5% human (Vector, Peterborough, UK). Likewise, deparaffination, fixation AB plasma supplemented with 100 U/ml interleukin -2 (R&D with 4% PFA/PBS, antigen retrieval in citrate-based buffer, and Systems, Minneapolis, MN, USA). The aggressive B-cell antibody stains as above were performed on paraffin tissue lymphoma/leukemia cell lines Balm3, Raji, Karpas 422, Ramos, sections arranged in multi-tissue arrays according to standard SuDHL4 (DSMZ) as well as the Hodgkin’s
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