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The clinical significance of ABCC3 as an imatinib transporter in chronic myeloid leukaemia

Leukemia volume 28, pages 1360–1363 (2014)Cite this article

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The advent of imatinib has revolutionised the treatment of chronic myeloid leukaemia (CML), but in contrast to clinical trial data population studies have demonstrated that ∼40% of these patients will develop resistance to imatinib. A proportion of these will progress to accelerated phase and/or blast crisis (BC).1 One cause of therapeutic resistance to imatinib is the emergence of BCR–ABL1 kinase domain mutations and gene amplification, but there are also BCR–ABL1-independent mechanisms of resistance including altered drug uptake and/or efflux.2 The ATP-binding cassette (ABC) transporters actively transport a variety of substances/drugs, and their physiological role as a defence mechanism against xenobiotics has been extensively investigated.2, 3 We and others have previously shown that imatinib is a substrate for the ABC efflux transporters ABCB1 (MDR1, p-glycoprotein) and ABCG2 (BCRP, breast cancer resistance protein), whereas its uptake is dependent on the expression/activity of the influx transporter SLC22A1 (hOCT1, human organic cation transporter-1).3, 4, 5, 6 However, additional transporters can affect treatment outcome in leukaemia, and an interplay between influx and efflux transporters could account for the observed inter-patient variability to drug response. A study by Hu et al.,7 using microarray analysis in acute myeloid leukaemia cell lines showed that hOCT1 mRNA expression was interrelated to the expression of the efflux ABCB1 (MDR1), ABCC3 (MRP3), ABCC4 (MRP4), ABCG2 (BCRP) and the influx OATP1A2 transporters. Radich et al.8 showed that ABCC3 expression was high in CML–BC patients with disease recurrence. None of these studies performed any functional ex vivo or in vitro work. This study was performed to further investigate the expression and function of ABC transporters involved in the cellular efflux of imatinib and their clinical significance in CML.

A panel of ABC transporters was analysed in peripheral blood leukocytes from four normal individuals and 90 newly diagnosed chronic-phase (CP) CML patients before imatinib treatment. The study was approved by the Liverpool Central Committee of the UK National Research Ethics Service and all individuals gave informed consent. Patients were classified into four groups based on their response to imatinib treatment at 12 months according to the European Leukemia Net 2009 recommendations as follows:9

  • Optimal (n=35); patients who achieve a complete cytogenetic response (CCR) on imatinib.

  • Suboptimal (n=23); patients who have achieved a major cytogenetic response but no CCR.

  • Failure (n=18); patients who fail to achieve a major cytogenetic response and/or switch to a second generation tyrosine kinase inhibitor.

  • BC (n=14); patients initially diagnosed in CP who subsequently progress to BC.

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Authors and Affiliations

  1. Department of Haematology, Molecular and Clinical Cancer Medicine, Royal Liverpool University Hospital, Liverpool, UK

    A Giannoudis, A Davies, R J Harris, C M Lucas & R E Clark

  2. Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK

    M Pirmohamed

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  1. A Giannoudis
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Correspondence to R E Clark.

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Giannoudis, A., Davies, A., Harris, R. et al. The clinical significance of ABCC3 as an imatinib transporter in chronic myeloid leukaemia. Leukemia 28, 1360–1363 (2014). https://doi.org/10.1038/leu.2014.38

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