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Journal of Cancer Research and Clinical Oncology

, Volume 140, Issue 8, pp 1323–1330 | Cite as

The clinical relevance and prognostic significance of adenosine triphosphate ATP-binding cassette (ABCB5) and multidrug resistance (MDR1) genes expression in acute leukemia: an Egyptian study

  • Hala M. Farawela
  • Mervat M. KhorshiedEmail author
  • Neemat M. Kassem
  • Heba A. Kassem
  • Hamdy M. Zawam
Original Article – Cancer Research

Abstract

Aim

Multidrug resistance (MDR1) represents a major obstacle in the chemotherapeutic treatment of acute leukemia (AL). Adenosine triphosphate ATP-binding cassette (ABCB5) and MDR1 genes are integral membrane proteins belonging to ATP-binding cassette transporters superfamily.

Purpose

The present work aimed to investigate the impact of ABCB5 and MDR1 genes expression on the response to chemotherapy in a cohort of Egyptian AL patients. The study included 90 patients: 53 AML cases and 37 ALL cases in addition to 20 healthy volunteers as controls.

Methods

Quantitative assessment of MDR1 and ABCB5 genes expression was performed by quantitative real-time polymerase chain reaction. Additional prognostic molecular markers were determined as internal tandem duplications of the FLT3 gene (FLT3-ITD) and nucleophosmin gene mutation (NPM1) for AML cases, and mbcr-abl fusion transcript for B-ALL cases.

Results

In AML patients, ABCB5 and MDR1 expression levels did not differ significantly between de novo and relapsed cases and did not correlate with the overall survival or disease-free survival. AML patients were stratified according to the studied genetic markers, and complete remission rate was found to be more prominent in patients having low expression of MDR1 and ABCB5 genes together with mutated NPM1 gene. In ALL patients, ABCB5 gene expression level was significantly higher in relapsed cases and MDR1 gene expression was significantly higher in patients with resistant disease.

Conclusion

In conclusion, the results obtained by the current study provide additional evidence of the role played by these genes as predictive factors for resistance of leukemic cells to chemotherapy and hence treatment outcome.

Keywords

MDR1 ABCB5 Gene expression AML ALL Chemotherapy 

Notes

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Asakura K, Uchida H, Miyachi H (2004) TEL/AML1 overcomes drug resistance through transcriptional repression of multidrug resistance-1 gene expression. Mol Cancer Res 2:339–347PubMedGoogle Scholar
  2. Bacher U, Kern W, Schoch C (2006) Evaluation of complete disease remission in acute myeloid leukemia: a prospective study based on cytomorphology, interphase fluorescence in situ hybridization, and immunophenotyping during follow-up in patients with acute myeloid leukemia. Cancer 106(4):839–847PubMedCrossRefGoogle Scholar
  3. Bai H, Li J, Jiang K, Liu X, Li C, Gai X (2014) The reverse effects of saikoside on multidrug resistance. Frontier and future development of information technology in medicine and education. Lect Notes Electr Eng 269:2273–2280CrossRefGoogle Scholar
  4. Beck WT, Grogan TM, Willman CL (1996) Methods to detect P-glycoprotein-associated multidrug resistance in patients’ tumors: consensus recommendations. Cancer Res 56:3010–3020PubMedGoogle Scholar
  5. Borst P, Evers R, Kool M, Wijnholds J (2000) A family of drug transporters: the multidrug resistance-associated proteins. J Natl Cancer Inst 92:1295–1302PubMedCrossRefGoogle Scholar
  6. Campos L, Guyotat D, Archimbaud E, Calmard-Oriol P, Tsuruo T, Troncy J, Treille D, Fiere D (1992) Clinical significance of multidrug resistance P-glycoprotein expression on acute nonlymphoblastic leukemia cells at diagnosis. Blood 79:473–476PubMedGoogle Scholar
  7. Chen KG, Szakács G, Annereau JP, Rouzaud F, Liang XJ (2005) Principal expression of two mRNA isoforms (ABCB 5 alpha and ABCB5 beta) of the ATP-binding cassette transporter gene ABCB5 in melanoma cells and melanocytes. Pigment Cell Res 18:102–112PubMedCentralPubMedCrossRefGoogle Scholar
  8. Dean M, Annilo T (2005) Evolution of the ATP-binding cassette (ABC) transporter superfamily in vertebrates. Annu Rev Genomics Hum Genet 6:123–142PubMedCrossRefGoogle Scholar
  9. Filipits M (2004) Mechanism of cancer: multidrug resistance. Drug Discov Today 1(2):229–234CrossRefGoogle Scholar
  10. Frank NY, Pendse SS, Lapchak PH (2003) Regulation of progenitor cell fusion by ABCB5 P-glycoprotein, a novel human ATP-binding cassette transporter. J Biol Chem 278:47156–47165PubMedCrossRefGoogle Scholar
  11. Frank NY, Margaryan A, Huang Y, Schatton T, Waaga-Gasser AM (2005) ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma. Cancer Res 65:4320–4333PubMedCrossRefGoogle Scholar
  12. Fujimaki S, Funato T, Harigae H, Fujiwara J, Kameoka J, Meguro K, Kaku M, Sasaki T (2002) Quantitative analysis of a MDR1 transcript for prediction of drug resistance in acute leukemia. Clin Chem 48(6):811–817PubMedGoogle Scholar
  13. Gekeler V, Frese G, Noller A (1992) Mdr1/P-glycoprotein, topoisomerase, and glutathione-S-transferase pi gene expression in primary and relapsed state adult and childhood leukaemias. Br J Cancer 66:507–517PubMedCentralPubMedCrossRefGoogle Scholar
  14. Gholami A, Salarilak S, Hejazi S, Khalkhali HR (2011) Parental risk factors of childhood acute leukemia: a case-control study. J Res Health Sci 11(2):69–76PubMedGoogle Scholar
  15. Gottesman MM (2002) Mechanisms of cancer drug resistance. Annu Rev Med 53:615–627PubMedCrossRefGoogle Scholar
  16. Gurbuxani S, Sazawal S, Arya LS, Raina V, Marie JP, Bhargava M (2000) MDR1 mRNA expression in young patients with acute lymphoblastic leukemia. Br J Haematol 109:895–905CrossRefGoogle Scholar
  17. Hart SM, Ganeshaguru K, Hoffbrand AV, Prentice HG, Mehta AB (1994) Expression of the multidrug resistance- associated protein (MRP) in acute leukaemia. Leukemia 8:2163–2168PubMedGoogle Scholar
  18. Huang Y, Anderle P, Bussey KJ, Barbacioru C, Shankavaram U, Dai Z, Reinhold WC, Papp A, Weinstein JN, Sadee W (2004) Membrane transporters and channels: role of the transportome in cancer chemosensitivity and chemoresistance. Cancer Res 64(12):4294–4301PubMedCrossRefGoogle Scholar
  19. Huh HJ, Park CJ, Jang S, Seo EJ, Chi HS, Lee JH, Lee KH, Seo JJ, Moon HN, Ghim T (2006) 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 21:253–258PubMedCentralPubMedCrossRefGoogle Scholar
  20. Illmer T, Schuler US, Thiede C, Schwarz UI, Kim RB, Gotthard S, Freund D, Schakel U, Ehninger G, Schaich M (2002) MDR1 gene polymorphisms affect therapy outcome in acute myeloid leukemia patients. Cancer Res 62:4955–4962PubMedGoogle Scholar
  21. Ito Y, Tanimoto M, Kumazawa T (1989) Increased P-glycoprotein expression and multidrug-resistant gene (mdr1) amplification are infrequently found in fresh acute leukemia cells: sequential analysis of 15 cases at initial presentation and relapsed stage. Cancer 63:1534–1538PubMedCrossRefGoogle Scholar
  22. Jiang EZ, Chang YJ, Lee JW, Lee WK, Kim JS, Sohn SK, Lee KB, Suh JS (1998) MDR1 gene expression in de novo acute leukemia cells: correlation with CD markers and treatment outcome. J Korean Med Sci 13:617–622PubMedCentralPubMedGoogle Scholar
  23. Kibria G, Hatakeyama H, Harashima H (2014) Cancer multidrug resistance: mechanisms involved and strategies for circumvention using a drug delivery system. Arch Pharm Res 37(1):4–15PubMedCrossRefGoogle Scholar
  24. Kourti M, Vavatsi N, Gombakis N, Tzimagiorgis G, Sidi V, Koliouskas D, Athanassiadou F (2006) Increased expression of multidrug resistance gene (MDR1) at relapse in a child with acute lymphoblastic leukemia. Pediatr Hematol Oncol 23(6):489–494PubMedCrossRefGoogle Scholar
  25. Kourti M, Vavatsi N, Gombakis N, Sidi V, Tzimagiorgis V, Papageorgiou T, Koliouskas D, Athanassiadou F (2007) Expression of multidrug resistance 1 (MDR1), multidrug resistance-related protein 1 (MRP1), lung resistance protein (LRP), and breast cancer resistance protein (BCRP) genes and clinical outcome in childhood acute lymphoblastic leukemia. Int J Hematol 86(2):166–173PubMedCrossRefGoogle Scholar
  26. Larsen AK, Escargueil AE, Skladanowski A (2000) Resistance mechanisms associated with altered intracellular distribution of anticancer agents. Pharmacol Ther 85:217–229PubMedCrossRefGoogle Scholar
  27. Lehne G, Grasmo-Wendler UH, Berner JM, Meza-Zepeda LA, Adamsen BL (2009) Upregulation of stem cell genes in multidrug-resistant K562 leukemia cells. Leuk Res 33:1379–1385PubMedCrossRefGoogle Scholar
  28. Leith CP, Kopecky KJ, Chen IM, Eijdems L, Slovak ML, McConnell TS, Head DR, Weick J, Grever MR, Appelbaum FR, Willman CL (1999) Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia: a Southwest Oncology Group Study. Blood 94(3):1086–1099PubMedGoogle Scholar
  29. Lilakos K, Viniou NA, Mavrogianni D, Vassilakopoulos TP, Dimopoulou MN, Plata E, Angelopoulou MK, Variami E, Stavrogianni N, Liapi D, Xilouri I, Galanopoulos A, Ageloudi M, Panayiotidis P, Voulgarelis M, Rombos J, Meletis J, Yataganas X, Pangalis GA (2006) FLT3 overexpression in acute promyelocytic leukemia patients without detectable FLT3-ITD or codon 835-836 mutations: a Pilot Study. Anticancer Res 26:1201–1208PubMedGoogle Scholar
  30. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C (T)) method. Methods 25:402–408PubMedCrossRefGoogle Scholar
  31. Lu Y, Jin R, Yang K, Sun L, Xiao Y, Pang X (2008) Detection and clinical significance of multidrug resistance-1 mRNA in bone marrow cells in children with acute lymphoblastic leukemia by real-time fluorescence quantitative RT-PCR. J Nanjing Med Univ 22(3):153–158CrossRefGoogle Scholar
  32. Luqmani YA (2005) Mechanisms of drug resistance in cancer chemotherapy. Med Princ Pract 14(1):35–48PubMedCrossRefGoogle Scholar
  33. Marie JP, Zittoun R, Sikic BI (1991) Multidrug resistance (mdr1) gene expression in adult acute leukemias: correlations with treatment outcome and in vitro drug sensitivity. Blood 78:586–592PubMedGoogle Scholar
  34. Milane L, Duan Z, Amiji M (2011) Therapeutic efficacy and safety of paclitaxel/lonidamine loaded EGFR-targeted nanoparticles for the treatment of multi-drug resistant cancer. PLoS One 6(9):e24075PubMedCentralPubMedCrossRefGoogle Scholar
  35. Moraes AR, Maranho CK, Rauber GS, Santos-Silva MA (2013) Importance of detecting multidrug resistance proteins in acute leukemia prognosis and therapy. J Clin Lab Anal 27:62–71PubMedCrossRefGoogle Scholar
  36. Pirker R, Wallner J, Geissler K, Linkesch W, Haas OA, Bettelheim P, Hopfner M, Scherrer R, Valent P, Havelec L (1991) MDR1 gene expression and treatment outcome in acute myeloid leukemia. J Natl Cancer Inst 83(10):708–712PubMedCrossRefGoogle Scholar
  37. Sato H, Preisler H, Day R (1990) MDR1 transcript levels as an indication of resistant disease in acute myelogenous leukaemia. Br J Haematol 75:340–345PubMedCrossRefGoogle Scholar
  38. Schaich M, Soucek S, Thiede C, Ehninger G, Illmer T (2004) MDR1 and MRP1 gene expression are independent predictors for treatment outcome in adult acute myeloid leukaemia. Br J Haematol 128:324–332CrossRefGoogle Scholar
  39. Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM (2008) Identification of cells initiating human melanomas. Nature 451:345–349PubMedCentralPubMedCrossRefGoogle Scholar
  40. Swerdlow SH, Campo E, Harris NL (2008) WHO classification of tumours of haematopoietic and lymphoid tissues. IARC Press, LyonGoogle Scholar
  41. Woodahl EL, Ho RJY (2004) The role of MDR1 genetic polymorphisms in interindividual variability in P-glycoprotein expression and function. Curr Drug Metab 5(1):11–19PubMedCrossRefGoogle Scholar
  42. Xu B, Song XY, Li L, Xu WJ, Tang JH (2008) The significance of quantification of MDR1 and WT1 gene expression in acute myeloid leukemia. Zhonghua Nei Ke Za Zhi 47(3):221–224PubMedGoogle Scholar
  43. Yang M, Li W, Fan D, Yan Y, Zhang X, Zhang Y, Xiong D (2012) Expression of ABCB5 gene in hematological malignances and its significance. Leuk Lymphoma 53(6):1211–1215PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Hala M. Farawela
    • 1
  • Mervat M. Khorshied
    • 1
    • 3
    Email author
  • Neemat M. Kassem
    • 1
  • Heba A. Kassem
    • 1
  • Hamdy M. Zawam
    • 2
  1. 1.Department of Clinical and Chemical Pathology, Faculty of MedicineCairo UniversityCairoEgypt
  2. 2.Department of Oncology, Faculty of MedicineCairo UniversityCairoEgypt
  3. 3.Kasr Al Ainy Teaching HospitalCairoEgypt

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