Abstract
The ABCB1 gene encodes for P-glycoprotein (P-gp), an efflux pump for a variety of xenobiotics. The role of ABCB1 polymorphisms in acute myeloid leukemia (AML) outcomes of standard chemotherapy (cytarabine plus anthracyclines) remains controversial. A systematic search was made of studies evaluating the association between ABCB1 polymorphisms 1236C>T, 2677G>T/A and 3435C>T and effectiveness variables. We found seven cohort studies (1241 patients) showing a significantly higher overall survival (OS) among carriers of the variant allele of 1236C>T at year 4 (odds ratio (OR): 1.47, 95% confidence interval (CI): 1.07–2.01), 2677G>T/A at years 4–5 (OR: 1.37, 95% CI: 1.01–1.86) and 3435C>T at years 3 (OR: 1.41, 95% CI: 1.03–1.94) and 4–5 (OR: 1.42, 95% CI: 1.05–1.91). In the subgroup analysis according to ethnicity, Caucasians carrying variant allele showed consistent results in OS. ABCB1 influence upon complete remission could not be demonstrated. Future studies based on larger populations and multiethnic groups should help clarify the effect of P-gp polymorphisms upon other outcomes.
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References
Löwenberg B . Acute myeloid leukemia: the challenge of capturing disease variety. Hematology Am Soc Hematol Educ Program 2008: 1–11.
Huntly B, Gilliland G . Pathobiology of acute myeloid leukemia. In: Hoffman (ed.) Hematology. Basic principles and practice. Churchill Livingstone: Philadelphia, 2005, pp 1057–1069.
Bodor M, Kelly EJ, Ho RJ . Characterization of the human MDR1 gene. AAPS J 2005; 7: E1–E5.
Allikmets R, Gerrard B, Hutchinson A, Dean M . Characterization of the human ABC superfamily: isolation and mapping of 21 new genes using the expressed sequence tags database. Hum Mol Genet 1996; 5: 1649–1655.
Yamada O, Ozaki K, Furukawa T, Machida M, Wang YH, Motoji T et al. Activation of STAT5 confers imatinib resistance on leukemic cells through the transcription of TERT and MDR1. Cell Signal 2011; 23: 1119–1127.
Johnstone RW, Ruefli AA, Smyth MJ . Multiple physiological functions for multidrug transporter P-glycoprotein? Trends Biochem Sci 2000; 25: 1–6.
Breier A, Barancik M, Sulova Z, Uhrik B . P-glycoprotein—implications of metabolism of neoplastic cells and cancer therapy. Curr Cancer Drug Targets 2005; 5: 457–468.
Samdani A, Vijapurkar U, Grimm MA, Spier CS, Grogan TM, Glinsmann-Gibson BJ et al. Cytogenetics and P-glycoprotein (PGP) are independent predictors of treatment outcome in acute myeloid leukemia (AML). Leukemia Res 1996; 20: 175–180.
Leith CP, Kopecky KJ, Chen IM, Eijdems L, Slovak ML, McConnell TS et al. Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/Pglycoprotein, MRP1, and LRP in acute myeloid leukemia: a Southwest Oncology Group Study. Blood 1999; 94: 1086–1099.
Leith CP, Kopecky KJ, Godwin J, McConnell T, Slovak ML, Chen IM et al. Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study. Blood 1997; 89: 3323–3329.
Benderra Z, Faussat AM, Sayada L, Perrot JY, Chaoui D, Marie JP et al. Breast cancer resistance protein and P-glycoprotein in 149 adult acute myeloid leukemias. Clin Cancer Res 2004; 10: 7896–7902.
Wuchter C, Leonid K, Ruppert V, Schrappe M, Buchner T, Schoch C et al. Clinical significance of P-glycoprotein expression and function for response to induction chemotherapy, relapse rate and overall survival in acute leukemia. Haematologica 2000; 85: 711–721.
Schaich M, Soucek S, Thiede C, Ehninger G, Illmer T . MDR1 and MRP1 gene expression are independent predictors for treatment outcome in adult acute myeloid leukaemia. Br J Haematol 2005; 128: 324–332.
Damiani D, Tiribelli M, Calistri E, Geromin A, Chiarvesio A, Michelutti A et al. The prognostic value of P-glycoprotein (ABCB) and breast cancer resistance protein (ABCG2) in adults with de novo acute myeloid leukemia with normal karyotype. Haematologica 2006; 91: 825–828.
Huh HJ, Park CJ, Jang S, Seo EJ, Chi HS, Lee JH et al. Prognostic significance of multidrug resistance gene 1 (MDR1), multidrug resistance-related protein (MRP) and lung resistance protein (LRP) mRNA expression in acute leukemia. J Korean Med Sci 2006; 21: 253–258.
Michieli M, Damiani D, Ermacora A, Masolini P, Raspadori D, Visani G et al. P-glycoprotein, lung resistance-related protein and multidrug resistance associated protein in de novo acute non-lymphocytic leukaemias biological and clinical implications. Br J Haematol 1999; 104: 328–335.
Shi P, Zha J, Guo X, Chen F, Fan Z, Huang F et al. Idarubicin is superior to daunorubicin in remission induction of de novo acute myeloid leukemia patients with high MDR1 expression. Pharmacogenomics 2013; 14: 17–23.
Sievers EL, Smith FO, Woods WG, Lee JW, Bleyer WA, Willman CL et al. Cell surface expression of the multidrug resistance Pglycoprotein (P-170) as detected by monoclonal antibody MRK-16 in pediatric acute myeloid leukemia fails to define a poor prognostic group: a report from the Childrens Cancer Group. Leukemia 1995; 9: 2042–2048.
Steinbach D, Furchtbar S, Sell W, Lengemann J, Hermann J, Zintl F et al. Contrary to adult patients, expression of the multidrug resistance gene (MDR1) fails to define a poor prognostic group in childhood AML. Leukemia 2003; 17: 470–471.
Wang D, Johnson AD, Papp AC, Kroetz DL, Sadee W . Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenet Genomics 2005; 15: 693–704.
Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A et al. Functional polymorphisms of the human multidrug- resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 2000; 97: 3473–3478.
Hitzl M, Drescher S, van der Kuip H, Schäffeler E, Fischer J, Schwab M et al. The C3435T mutation in the human MDR1 gene is associated with altered efflux of the P-glycoprotein substrate rhodamine 123 from CD56+ natural killer cells. Pharmacogenetics 2001; 11: 293–298.
Seedhouse CH, Grundy M, White P, Li Y, Fisher J, Yakunina D et al. Sequential influences of leukemia-specific and genetic factors on p-glycoprotein expression in blasts from 817 patients entered into the National Cancer Research Network acute myeloid leukemia 14 and 15 trials. Clin Cancer Res 2007; 13: 7059–7066.
Jamroziak K, Balcerczak E, Cebula B, Janus A, Mirowski M, Robak T . No influence of 3435C>T ABCB1 (MDR1) gene polymorphism on risk of adult acute myeloid leukemia and P-glycoprotein expression in blast cells. Ther Drug Monit 2006; 28: 707–711.
Nakamura T, Sakaeda T, Horinouchi M, Tamura T, Aoyama N, Shirakawa T et al. Effect of the mutation (C3435T) at exon 26 of the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy Japanese subjects. Clin Pharmacol Ther 2002; 71: 297–303.
Illmer T, Schuler US, Thiede C, Schwarz UI, Kim RB, Gotthard S et al. MDR1 gene polymorphisms affect therapy outcome in acute myeloid leukemia patients. Cancer Res 2002; 62: 4955–4962.
Kim DH, Park JY, Sohn SK, Lee NY, Baek JH, Jeon SB et al. Multidrug resistance-1 gene polymorphisms associated with treatment outcomes in de novo acute myeloid leukemia. Int J Cancer 2006; 118: 2195–2201.
Sakaeda T, Nakamura T, Horinouchi M, Kakumoto M, Ohmoto N, Sakai T et al. MDR1 genotype-related pharmacokinetics of digoxin after single oral administration in healthy Japanese subjects. Pharm Res 2001; 18: 1400–1404.
Lamba J, Strom S, Venkataramanan R, Thummel KE, Lin YS, Liu W et al. MDR1 genotype is associated with hepatic cytochrome P4503A4 basal and induction phenotype. Clin Pharmacol Ther 2006; 79: 325–338.
Kurata Y, Ieiri I, Kimura M, Morita T, Irie S, Urae A et al. Role of human MDR1 gene polymorphism in bioavailability and interactionof digoxin, a substrate of P-glycoprotein. Clin Pharmacol Ther 2002; 72: 209–219.
Doxani C, Voulgarelis M, Zintzaras E . MDR1 mRNA expression and MDR1 gene variants as predictors of response to chemotherapy in patients with acute myeloid leukaemia: a meta-analysis. Biomarkers 2013; 18: 425–435.
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009; 339: b2700.
Gréen H, Falk IJ, Lotfi K, Paul E, Hermansson M, Rosenquist R et al. Association of ABCB1 polymorphisms with survival and in vitro cytotoxicty in de novo acute myeloid leukemia with normal karyotype. Pharmacogenomics J 2012; 12: 111–118.
Hampras SS, Sucheston L, Weiss J, Baer MR, Zirpoli G, Singh PK et al. Genetic polymorphisms of ATP-binding cassette (ABC) proteins, overall survival and drug toxicity in patients with Acute Myeloid Leukemia. Int J Mol Epidemiol Genet 2010; 1: 201–207.
Hur EH, Lee JH, Lee MJ, Choi SJ, Lee JH, Kang MJ et al. C3435T polymorphism of the MDR1 gene is not associated with P-glycoprotein function of leukemic blasts and clinical outcome in patients with acute myeloid leukemia. Leuk. Res 2008; 32: 1601–1604.
Scheiner MA, da Cunha Vasconcelos F, da Matta RR, Dal Bello Figueira R Jr, Maia RC . ABCB1 genetic variation and P-glycoprotein expression/activity in a cohort of Brazilian acute myeloid leukemia patients. J Cancer Res Clin Oncol 2012; 138: 959–969.
van der Holt B, Van den Heuvel-Eibrink MM, Van Schaik RH, van der Heiden IP, Wiemer EA, Vossebeld PJ et al. ABCB1 gene polymorphisms are not associated with treatment outcome in elderly acute myeloid leukemia patients. Clin Pharmacol Ther 2006; 80: 427–439.
Berman E, McBride M . Comparative cellular pharmacology of daunorubicin and idarubicin in human multidrug-resistant leukemia cells. Blood 1992; 79: 3267–3273.
Tsimberidou AM, Paterakis G, Androutsos G, Anagnostopoulos N, Galanopoulos A, Kalmantis T et al. Evaluation of the clinical relevance of the expression and function of P-glycoprotein, multidrug resistance protein and lung resistance protein in patients with primary acute myelogenous leukemia. Leuk Res 2002; 26: 143–154.
Lacayo NJ, Duran GE, Sikic BI . Modulation of resistance to idarubicin by the cyclosporin PSC 833 (valspodar) in multidrug-resistant cells. J Exp Ther Oncol 2003; 3: 127–135.
Sheng X, Zhang L, Tong N, Luo D, Wang M, Xu M et al. MDR1 C3435T polymorphism and cancer risk: a meta-analysis based on 39 case-control studies. Mol Biol Rep 2012; 39: 7237–7249.
Zhang BB, Xuan C, Deng KF, Wu N, Lun LM . Association between the MDR1 gene variant C3435T and risk of leukaemia: a meta-analysis. Eur J Cancer Care (Engl) 2013; 22: 617–625.
Yan Y, Liang H, Xie L, He Y, Li M, Li R et al. Association of MDR1 G2677T polymorphism and leukemia risk: evidence from a meta-analysis. Tumour Biol 2014; 35: 2191–2197.
Acknowledgements
Work supported by grant of the Pharmacy and Hematology Departments and the Pharmacogenetic Unit of ‘Instituto Investigación Sanitaria La Fe’ and ‘Área del Medicamento’ of ‘Hospital Universitari i Politècnic La Fe’, Valencia, Spain. This study was supported in part by research funding from the ‘Instituto Carlos III’ grant’ PIE13/00046’ and ‘Instituto Investigación Sanitaria La Fe’ 2013/0331.
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Megías-Vericat, J., Rojas, L., Herrero, M. et al. Influence of ABCB1 polymorphisms upon the effectiveness of standard treatment for acute myeloid leukemia: A systematic review and meta-analysis of observational studies. Pharmacogenomics J 15, 109–118 (2015). https://doi.org/10.1038/tpj.2014.80
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DOI: https://doi.org/10.1038/tpj.2014.80
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