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Sensitivity and Resistance to Therapy

Intracellular ABC transporter A3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration

Leukemia volume 22, pages 1576–1586 (2008)Cite this article

Abstract

Multidrug resistance (MDR) seriously limits the efficacy of chemotherapy in patients with cancer and leukemia. Active transport across membranes is essential for such cellular drug resistance, largely provided by ATP-binding cassette (ABC) transport proteins. Intracellular drug sequestration contributes to MDR; however, a genuine intracellular ABC transport protein with MDR function has not yet been identified. Analyzing the intrinsic drug efflux capacity of leukemic stem cells, we found the ABC transporter A3 (ABCA3) to be expressed consistently in acute myeloid leukemia (AML) samples. Greater expression of ABCA3 is associated with unfavorable treatment outcome, and in vitro, elevated expression induces resistance toward a broad spectrum of cytostatic agents. ABCA3 remains localized within the limiting membranes of lysosomes and multivesicular bodies, in which cytostatics are efficiently sequestered. In addition to AML, we also detected ABCA3 in a panel of lymphohematopoietic tissues and transformed cell lines. In conclusion, we identified subcellular drug sequestration mediated by the genuinely intracellular ABCA3 as being a clinically relevant mechanism of intrinsic MDR.

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Acknowledgements

BC designed and performed research, and analyzed data; RK, UR and SC performed research; NC, NI and NB contributed vital new reagents; DW performed research; DR provided vital reagents; AZ analyzed data; SS, WK, FK and LT contributed vital reagents and analyzed data; GGW designed research, analyzed data and wrote the paper. We thank Birgit Juenemann and Boguslawa Sadowski of the flow cytometry core facility at the University of Goettingen and York Hildebrandt for technical assistance, as well as Andrew Entwistle for his editing and proofreading of thepaper. Financial support for this research was provided to GW from the Deutsche Jose-Carreras Leukaemiestiftung and to BC from the research funding program of the Faculty of Medicine, Georg-August-University Goettingen.

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Authors and Affiliations

  1. Department of Hematology and Oncology, Georg-August-University Goettingen, Goettingen, Germany

    B Chapuy, R Koch, U Radunski, S Corsham, L Truemper & G G Wulf

  2. Department of Physiology, University of Pennsylvania, Philadelphia, PA, USA

    N Cheong

  3. Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    N Inagaki

  4. Department of Physiology, Akita University School of Medicine, Akita, Japan

    N Ban

  5. Department of Neurobiology, Max Planck Institute for Biophysical Chemistry, Goettingen, Germany

    D Wenzel

  6. Department of Pediatrics, Medizinische Hochschule Hannover, Hannover, Germany

    D Reinhardt

  7. Department of Medical Statistics, Georg-August-University Goettingen, Goettingen, Germany

    A Zapf

  8. Department of Pathology, Georg-August-University Goettingen, Goettingen, Germany

    S Schweyer

  9. Department of Hematopathology and Lymph Node Registry, University of Schleswig- Holstein, Kiel, Germany

    F Kosari & W Klapper

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  1. B Chapuy
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Correspondence to G G Wulf.

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None of the authors have any financial interest related to this work.

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Chapuy, B., Koch, R., Radunski, U. et al. Intracellular ABC transporter A3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration. Leukemia 22, 1576–1586 (2008). https://doi.org/10.1038/leu.2008.103

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