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Association of ABCB1 polymorphisms with survival and in vitro cytotoxicty in de novo acute myeloid leukemia with normal karyotype

The Pharmacogenomics Journal volume 12, pages 111–118 (2012)Cite this article

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Abstract

Overexpression of the multi-drug transporter P-glycoprotein, encoded by the ABCB1 gene, is a clinically relevant problem in acute myeloid leukemia (AML). Polymorphisms in ABCB1 might contribute to cancer risk and therapeutic response. We therefore investigated the influence of polymorphisms G1199A, C1236T, G2677T/A and C3435T on cancer susceptibility, in vitro cytotoxicity and overall survival in 100 de novo AML patients with normal karyotype. Patients with 1236C/C or 2677G/G genotypes showed poorer survival than patients with other genotypes (P=0.03 and P=0.02, respectively). Both these genotypes were significant factors for survival in multivariate analysis, along with age, NPM1 and FLT3 mutation status. In vitro cytotoxicity studies demonstrated that leukemic cells from 1236T/T and 2677T/T patients were significantly more susceptible to mitoxantrone (P=0.02), and tended to be more susceptible to etoposide and daunorubicin (P=0.07–0.09), but not to cytarabine. No significant difference in allele frequencies was found between patients and healthy volunteers (n=400).

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Acknowledgements

We thank Kerstin Willander for technical help and assistance during sample collection. We also thank Mats Fredriksson, Linköping University for his help with the statistics. This work was supported by grants from the Swedish Cancer Society, Swedish Research Council—Medicine, Cancer Society in Stockholm, Karolinska Institutet, and the County Council in Östergötland.

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Authors and Affiliations

  1. Department of Medical and Health Sciences, Clinical Pharmacology, Faculty of Health Sciences, Linköpings Universitet, Linköping, Sweden

    H Gréen, I J Falk & K Lotfi

  2. Department of Hematology, Faculty of Health Sciences, Linköpings Universitet, Linköping, Sweden

    K Lotfi

  3. Department of Hematology, Karolinska University Hospital and Karolinska Institutet, Huddinge, Sweden

    E Paul, C Paul & H Nahi

  4. Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden

    M Hermansson & R Rosenquist

  5. Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

    R Rosenquist

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  1. H Gréen
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Correspondence to H Gréen.

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Author contributions

HG was the principal investigator and takes primary responsibility for the manuscript. HG was also involved in conception and design, collection and compilation of data, data analysis and writing the manuscript; IJF: collection and compilation of data, data analysis, and helping write the manuscript; KL: conception, data analysis and patient recruitment; MH: FLT3 and NPM1 analysis; RR: data analysis, strategic suggestions, writing the manuscript, FLT3 and NPM1 analysis; EP and CP: collection of data and patient recruitment; HN: conception, data analysis and patient recruitment.

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Gréen, H., Falk, I., Lotfi, K. et al. Association of ABCB1 polymorphisms with survival and in vitro cytotoxicty in de novo acute myeloid leukemia with normal karyotype. Pharmacogenomics J 12, 111–118 (2012). https://doi.org/10.1038/tpj.2010.79

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