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Polymorphism in multidrug resistance-associated protein gene 3 is associated with outcomes in childhood acute lymphoblastic leukemia

The Pharmacogenomics Journal volume 12, pages 386–394 (2012)Cite this article

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Abstract

Multidrug resistance-related proteins (MRPs) 2, 3 and 5 are involved in the efflux of drugs used in acute lymphoblastic leukemia (ALL) treatment. Polymorphisms of these genes were investigated for an association with treatment responses in 273 childhood ALL patients. The MRP3 A−189 allele of the regulatory AT polymorphism was associated with reduced event-free survival (P=0.01). The results remained significant after adjustment for multiple comparisons and in the multivariate analysis. Among patients with an event, the A−189 carriers had significantly higher methotrexate plasma levels (P=0.03). MRP3 A−189 also conferred four times higher risk of a relapse in central nervous system (P=0.01). Patients with this allele tended to have lower frequency of thrombocytopenia grade 2 (P=0.06). Gene reporter assay showed that the haplotype tagged by the A−189 had higher promoter activity (P⩽0.01). In conclusion, MRP3 A−189 T polymorphism was associated with treatment responses in ALL, likely due to the change in MRP3 efflux.

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Acknowledgements

We are thankful to all patients and their parents who consented to participate in genetics study related to leukemia. This work was supported by grants from the Leukaemia Lymphoma Society of Canada, CIHR, Research Centre of CHU Sainte-Justine, Charles Bruneau Foundation and Centre d’Excellence en Oncologie Pédiatrique et en Soins Palliatifs. MK and DS are scholars of the Fonds de la Recherche en Santé du Québec, MA is scholar of the Swiss National Fund, Charles Bruneau and Telemaque foundations. Gene reporter assay was carried out in part within the project of Genome Quebec/Genome Canada: gene regulators in disease.

Author contributions: MA, GS, ML, JR, VG performed experiments, MA, AM, CL contributed to the retrieval of clinical data; MA, VG and MK performed the analysis; MK designed the research; DS contributed in part to the gene reporter assay; MA and MK drafted the article; all authors contributed to the interpretation of data and revised the paper critically.

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Authors and Affiliations

  1. Research Center, CHU Sainte-Justine, Montreal, Quebec, Canada

    M Ansari, G Sauty, M Labuda, V Gagné, J Rousseau, A Moghrabi, C Laverdière, D Sinnett & M Krajinovic

  2. Department of Pediatrics, University Hospital of Geneva, Geneva, Switzerland

    M Ansari

  3. Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada

    A Moghrabi, C Laverdière, D Sinnett & M Krajinovic

  4. Department of Pharmacology, University of Montreal, Montreal, Quebec, Canada

    M Krajinovic

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Ansari, M., Sauty, G., Labuda, M. et al. Polymorphism in multidrug resistance-associated protein gene 3 is associated with outcomes in childhood acute lymphoblastic leukemia. Pharmacogenomics J 12, 386–394 (2012). https://doi.org/10.1038/tpj.2011.17

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