P-glycoprotein and multidrug resistance-associated protein-1 expression in acute myeloid leukemia: Biological and prognosis implications
Lenilton Silva da Silveira Júnior
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Search for more papers by this authorVictor de Lima Soares
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Search for more papers by this authorAlessandra Suelen Jardim da Silva
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Faculdade de Ciências da Saúde do Trairi/UFRN, Santa Cruz, Brazil
Search for more papers by this authorErica Aires Gil
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Search for more papers by this authorMaria das Graças Pereira de Araújo
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Laboratório de Citometria de Fluxo, Hemocentro Dalton Cunha, Natal, Brazil
Search for more papers by this authorCiro Alexandre Merces Gonçalves
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Laboratório de Citometria de Fluxo, Hemocentro Dalton Cunha, Natal, Brazil
Search for more papers by this authorAldair de Souza Paiva
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Search for more papers by this authorTaissa Maria Moura de Oliveira
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Search for more papers by this authorGustavo Henrique de Medeiros Oliveira
Laboratório de Citometria de Fluxo, Hemocentro Dalton Cunha, Natal, Brazil
Search for more papers by this authorDany Geraldo Kramer Cavacanti e Silva
Faculdade de Ciências da Saúde do Trairi/UFRN, Santa Cruz, Brazil
Search for more papers by this authorTelma Maria de Araújo Moura Lemos
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Search for more papers by this authorIvanise Marina Moretti Rebecchi
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Search for more papers by this authorValeria Soraya de Farias Sales
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Search for more papers by this authorAndré Ducati Luchessi
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Search for more papers by this authorCorresponding Author
Geraldo Barroso Cavalcanti Júnior
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Laboratório de Citometria de Fluxo, Hemocentro Dalton Cunha, Natal, Brazil
Correspondence
Geraldo Barroso Cavalcanti Júnior, Laboratório de Imunologia Clínica, Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Centro de Ciências da Saúde, Universidade Federal do Rio Grande do Norte, 1th floor, Avenida Gustavo Cordeiro de Farias S/N, CEP: 59010-180, Natal, RN, Brazil.
Email: [email protected]
Search for more papers by this authorLenilton Silva da Silveira Júnior
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Search for more papers by this authorVictor de Lima Soares
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Search for more papers by this authorAlessandra Suelen Jardim da Silva
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Faculdade de Ciências da Saúde do Trairi/UFRN, Santa Cruz, Brazil
Search for more papers by this authorErica Aires Gil
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Search for more papers by this authorMaria das Graças Pereira de Araújo
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Laboratório de Citometria de Fluxo, Hemocentro Dalton Cunha, Natal, Brazil
Search for more papers by this authorCiro Alexandre Merces Gonçalves
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Laboratório de Citometria de Fluxo, Hemocentro Dalton Cunha, Natal, Brazil
Search for more papers by this authorAldair de Souza Paiva
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Search for more papers by this authorTaissa Maria Moura de Oliveira
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Search for more papers by this authorGustavo Henrique de Medeiros Oliveira
Laboratório de Citometria de Fluxo, Hemocentro Dalton Cunha, Natal, Brazil
Search for more papers by this authorDany Geraldo Kramer Cavacanti e Silva
Faculdade de Ciências da Saúde do Trairi/UFRN, Santa Cruz, Brazil
Search for more papers by this authorTelma Maria de Araújo Moura Lemos
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Search for more papers by this authorIvanise Marina Moretti Rebecchi
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Search for more papers by this authorValeria Soraya de Farias Sales
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Search for more papers by this authorAndré Ducati Luchessi
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Search for more papers by this authorCorresponding Author
Geraldo Barroso Cavalcanti Júnior
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte (DACT/UFRN), Natal, Brazil
Laboratório de Citometria de Fluxo, Hemocentro Dalton Cunha, Natal, Brazil
Correspondence
Geraldo Barroso Cavalcanti Júnior, Laboratório de Imunologia Clínica, Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Centro de Ciências da Saúde, Universidade Federal do Rio Grande do Norte, 1th floor, Avenida Gustavo Cordeiro de Farias S/N, CEP: 59010-180, Natal, RN, Brazil.
Email: [email protected]
Search for more papers by this authorLenilton Silva da Silveira Júnior and Victor de Lima Soares contributed equally to this article.
Abstract
Background
Despite the advances in the cure rate for acute myeloid leukemia (AML), a considerable number of patients die from the disease due to the occurrence of multidrug resistance (MDR). Overexpression of the transporter proteins, such as P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP), confers resistance to the treatment of these leukemias.
Methods
To analyze the expression of the Pgp and MRP1 in patients with AML and determine their correlation between expression and demographic, clinical, and laboratorial variables, bone marrow and peripheral blood samples from 346 patients with a diagnosis of AML were assessed for the expression of Pgp and MRP1 by flow cytometry.
Results
The expression of Pgp and MRP1 was found in 111 (32.1%) and 133 (38.4%) patients, respectively, with greater prevalence in older patients and lower in children, while also observing a high incidence in patients with refractory, recurrence, and secondary disease in comparison with the cases of de novo AML. Regarding the laboratory findings, we observed an association between the expression of Pgp and MRP1 and CD34, CD7, and also M7, M5a, and M2-AML of French-American-British classification.
Conclusions
The results showed that the detection of MDR phenotype by flow cytometry can be a molecular marker for prognosis of patients with AML.
CONFLICTS OF INTEREST
The authors participating in this manuscript declare that there is no conflict of interest of any kind.
REFERENCES
- 1Stavrovskaya AA. Cellular mechanism of multidrug resistance of tumor cells. Biochemistry. 2002; 65(1): 95-106
- 2Gottesman MM. Mechanisms of cancer resistance. Annu Rev Med. 2003; 53: 615-627
- 3Moraes AC, Maranhão GSR, Santos Silva MC. Importance of detecting multidrug resistance proteins in acute leukemia prognosis and therapy. J Clin Lab Anal. 2013; 100: 974-981
- 4Tafuri A, Gregory C, Petrucci MT, et al. MDR-1 protein expression is an independent predictor of complete remission in newly diagnosed adult acute lymphoblastic leukemia. Blood. 2002; 100: 974-981
- 5Renes J, de Vries EGE, Jansen PLM, Müler M. The (patho) physiological functions of the MRP family. Drug Res Update. 2003; 3: 289-302
- 6van den Heuvel-Eibrink MM, Wiemer EAC, Prins A, et al. Increased expression of the breast cancer resistance protein (BCRP) in relapsed or refractory acute myeloid leukemia (AML). Leukemia. 2002; 16: 833-839
- 7Cavalcanti Júnior GB, Cunha ALA. Estudo de resistência a drogas. In: Duarte AJS, Mirtes Sales M, Moraes VD, eds. Citometria de fluxo aplicações no laboratório clínico e de pesquisa. Chapter 57, S. Paulo, Brazil: Ed Atheneu; 2013: 591-610
- 8Leith CP, Kopecky KJ, Godwin J, 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
- 9Del Poeta G, Stasi R, Aronica G, et al. Clinical relevance of P-glicoprotein expression in de novo acute myeloid leukemia. Blood. 1996; 87(5): 1997-2004
- 10Figueiredo-Pontes LL, Pintão MCT, Oliveira LCO, et al. Determination of P-glycoprotein, MDR-Related Protein 1, breast cancer resistance protein, and lung-resistance protein expression in leukemic stem cells of Acute Myeloid Leukemia. Cytometry part B (Clin Cyt). 2008; 74B: 163-168
- 11Ying DU, Chen B. Detection approaches for multidrug resistance genes of leukemia. J Clin Lab Anal. 2013; 27: 62-71
- 12Huet S, Marie JP, Gualde N, et al. Reference method for detection of Pgp mediated multidrug resistance in human hematological malignancies: a method validated by the laboratories of the French Drug Resistance Network. Cytometry. 1998; 34: 248-256
10.1002/(SICI)1097-0320(19981215)34:6<248::AID-CYTO2>3.0.CO;2-X CAS PubMed Web of Science® Google Scholar
- 13Beck WT, Grogan TM, Willman CL, et al. Methods to detect P glycoprotein associated multidrug resistance in patients' tumors: consensus recommendations. Cancer Res. 1996; 56: 3010-3020
- 14Bennet JM, Catovsky D, Daniel MT, et al. Proposed revised criteria for the classification of acute myeloid leukemia. Annals Int Med. 1990; 103: 620-629
- 15Bain BJ, Swirsky D. Erythrocyte and leucocyte cytochemistry. In: BJ Bain, I Bates, MA Laffan, SM Lewis, eds. Dacie and Lewis Practical Haematology; chapter 15, 11th Ed. London, UK: Elsevier Churchill Livingstone; 2012: 333-352
10.1016/B978-0-7020-3408-4.00015-1 Google Scholar
- 16Bene MC, Castoldi G, Knap W, et al. Proposal for the immunological classification of acute leukemias. European group for the immunological characterization of leukemias (EGIL). Leukemia. 1995; 9: 1783-1786
- 17van Dongen JJM, Lhermitte L, Böttcher S, et al. Euro Flow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes. Leukemia. 2012; 26(9): 1908-1975
- 18Ikoma MVI, Sandes AF, Thiago LS, et al. First proposed panels on acute leukemia for four-color immunophenotyping by flow cytometry from the Brazilian group of flow cytometry-GBCFLUX. Cytometry part B (Clin Cyt). 2015; 88B: 194-203
10.1002/cytob.21175 Google Scholar
- 19Andrade Alves GV, Fernandes ALC, Freire JM, et al. Flow cytometry immunophenotyping evaluation in acute lymphoblastic leukemia: correlation to factors affecting clinic outcome. J Clin Lab Anal. 2012; 26: 431-440
- 20Cavalcanti Júnior GB, Scheiner MAM, Simôes Magluta EP, et al. p53 flow cytometry evaluation in leukemias: correlation to factors affecting clinic outcome. Cytometry part B (Clin Cyt). 2010; 78B(4): 253-259
- 21Cavalcanti Júnior GB, Vasconcelos FC, Faria GP, et al. Co-expression of p53 protein and MDR functional phenotype in leukemias: the predominant association in chronic myeloid leukemia. Cytometry Part B (Clin Cyt). 2004; 61B: 1-8
- 22Walter RB, Raden BW, Hong TC, et al. Multidrug resistance protein attenuates gemtuzumab ozogamicin–induced cytotoxicity in acute myeloid leukemia cells. Blood. 2003; 102(4): 1466-1473
- 23Broxterman HJ, Schuurhuis GJ. Transport proteins in drug resistance: detection and prognostic significance in acute myeloid leukemia. J Intern Med Suppl. 1997; 740: 147-151
- 24Zochbauer S, Schwarzinger I, Strobl H, et al. Relationship between MDR1 gene and surface markers in acute myeloid leukemia. Anticancer Res. 1997; 17(1B): 749-752
- 25Vasconcelos FC, Cavalcanti Júnior GB, Lani Silva K, et al. Contrasting features of MDR phenotype in leukemias by using two fluorochromes: implications for clinical practice. Leuk Res. 2007; 31: 445-454
- 26Suárez L, Vidriales MB, Garcia-Laraña J, et al. Multiparametric analysis of apoptotic and multidrug resistance phenotypes according to the blast cell maturation stage in elderly patients with acute myeloid leukemia. Haematologica. 2001; 86: 1287-1295
- 27Pirker R, Wallner J, Geissler K, et al. MDR1 gene expression and treatment outcome in acute myeloid leukemia. J Natl Cancer Inst. 1991; 83: 708-712
- 28Damiani D, Tiribelli M, Raspadori D, et al. The role of MDR-related proteins in the prognosis of adult acute myeloid leukaemia (AML) with normal karyotype. Hematol Oncol. 2007; 25: 38-43
- 29Legrand O, Zompi S, Jean-Yves P, et al. P-glycoprotein and multidrug resistance associated protein-1 activity in 132 acute myeloid leukemias according to FAB subtypes and cytogenetic risk groups. Haematologica. 2004; 89: 34-41
- 30Filipits M, Stranzl T, Pohl G, et al. Drug resistance factors in acute myeloid leukemia: a comparative analysis. Leukemia. 2000; 14: 68-76
- 31Kappelmayer J, Hevessy Z, Apjok A, Jakab KT. Prediction of therapy response and prognosis in leukemias by flow cytometry MDR assays. JIFCC. 2012; 23(4): 1-7
- 32Michieli M, Damiani D, Ermacora A, 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(2): 328-335
- 33Laupeze B, Amiot L, Drenou B, et al. High multidrug resistance protein activity in acute myeloid leukaemias is associated with poor response to chemotherapy and reduced patient survival. Br J Haematol. 2002; 116(4): 834-838
- 34van der Kolk DM, de Vries EGE, van Putten WLJ, et al. P-glycoprotein and multidrug resistance protein activities in relation to treatment outcome in acute myeloid leukemia. Clin Cancer Res. 2000; 6: 3205-3214
- 35van den Heuvel-Eibrink MM, van der Holt B, Burnett AK, et al. CD34-related coexpression of MDR1 and BCRP indicates a clinically resistant phenotype in patients with acute myeloid leukemia (AML) of older age. Ann Hematol. 2007; 86: 329-337
- 36Saraymen B, Çimen B, Çetin I, et al. Determination of P-glycoprotein expression by flow cytometry in hematological malignancies. Dicle Med J. 2016; 43(1): 33-38
10.5798/diclemedj.0921.2016.01.0634 Google Scholar
- 37Miwa H, Kita K, Nishii K, et al. Expression of MDR1 gene in acute leukemia cell: association with CD7+ acute myeloblastic leukemia/acute lymphoblastic leukemia. Blood. 1993; 82: 3445-3451
- 38Burger H, Nooter K, Zaman GJR, et al. Expression of multidrug resistance-associated protein (MRP) in acute and chronic leukemias. Leukemia. 1994; 8(6): 990-997
- 39Liu Bei, Li Li-Jun, Gong Xia, Zhang Wei, Zhang Hui, Zhao Li. Co-expression of ATP binding cassette transporters is associated with poor prognosis in acute myeloid leukemia. Oncol Lett. 2018; 15: 6671-6677
- 40Rothenberg M, Mickley L, Cole D. Expression of mdr1/Pgp gene in patients with acute lymphoblastic leukemia. Blood. 1989; 74: 1399-1395
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