Blood Res.  2015 Sep;50(3):154-159. 10.5045/br.2015.50.3.154.

MDR1/ABCB1 gene polymorphisms in patients with chronic myeloid leukemia

Affiliations
  • 1INFIBIOC-FFyB-UBA, Buenos Aires, Argentina. nadiatom@ffyb.uba.ar
  • 2Division Gastroenterologia Hospital de Clinicas "J. San Martin", Buenos Aires, Argentina.
  • 3Division Hematologia, Hospital Municipal "Ramos Mejia", Buenos Aires, Argentina.
  • 4Division Hematologia, Hospital de Clinicas "J. San Martin", Facultad de Medicina-UBA, Buenos Aires, Argentina.
  • 5Division Hemoterapia, Hospital de Clinicas "J. San Martin", Facultad de Medicina-UBA, Buenos Aires, Argentina.
  • 6Fundacion Investigar, Buenos Aires, Argentina.

Abstract

BACKGROUND
Tyrosine kinase inhibitors (TKIs) are the recommended treatment for patients with chronic myeloid leukemia (CML). The MDR1/ABCB1 gene plays a role in resistance to a wide spectrum of drugs, including TKIs. However, the association of MDR1/ABCB1 gene polymorphisms (SNPs) such as C1236T, G2677T/A, and C3435T with the clinical therapeutic evolution of CML has been poorly studied. We investigated these gene polymorphisms in CML-patients treated with imatinib, nilotinib and/or dasatinib.
METHODS
ABCB1-SNPs were studied in 22 CML-patients in the chronic phase (CP) and 2 CML-patients in blast crisis (BC), all of whom were treated with TKIs, and compared with 25 healthy controls using nested-PCR and sequencing techniques.
RESULTS
Seventeen different haplotypes were identified: 7 only in controls, 6 only in CML-patients, and the remaining 4 in both groups. The distribution ratios of homozygous TT-variants present on each exon between controls and CML-patients were 2.9 for exon 12, and 0.32 for the other 2 exons. Heterozygous T-variants were observed in all controls (100%) and 75% of CML-patients. Wt-haplotype (CC-GG-CC) was observed in 6 CML-patients (25%). In this wt-group, two were treated with nilotinib and reached a major molecular response. The remaining 4 cases had either a minimal or null molecular response, or developed bone marrow aplasia.
CONCLUSION
Our results suggest that SNPs of the MDR1/ABCB1 gene could help to characterize the prognosis and the clinical-therapeutic evolution of CML-patients treated with TKIs. Wt-haplotype could be associated with a higher risk of developing CML, and a worse clinical-therapeutic evolution.

Keyword

CML; TKIs; ABCB1; SNPs; BCR-ABL

MeSH Terms

Blast Crisis
Bone Marrow
Exons
Haplotypes
Humans
Leukemia, Myelogenous, Chronic, BCR-ABL Positive*
Polymorphism, Single Nucleotide
Prognosis
Protein-Tyrosine Kinases
Dasatinib
Imatinib Mesylate
Protein-Tyrosine Kinases

Figure

  • Fig. 1 Frequency distribution of haplotypes in CML-patients and controls. CML were 25% wt and 75% muted, while controls were 100% muted.

  • Fig. 2 Frequency of TT-homozygous variants in each exon studied in controls and CML-patients. a)P<0.01, Mann-Whitney test.

  • Fig. 3 Therapeutic responses of the 24 CML-patients at 12 months according to the TKI administered. Wt-haplotypes are indicated in each case. The remaining patients were T-variants. In three cases, therapeutic responses were not evaluated because the patients developed bone marrow aplasia, breast cancer, or early fatal blast crisis.

  • Fig. 4 Frequency of T-variants (with at least one T allele) in 22 CML-patients in the chronic phase according to their therapeutic response. a)P<0.001, X2-Fischer test.


Reference

1. Deininger MW, Goldman JM, Melo JV. The molecular biology of chronic myeloid leukemia. Blood. 2000; 96:3343–3356. PMID: 11071626.
Article
2. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010; 362:2251–2259. PMID: 20525993.
Article
3. Goldman JM, Melo JV. Chronic myeloid leukemia-advances in biology and new approaches to treatment. N Engl J Med. 2003; 349:1451–1464. PMID: 14534339.
4. Nagar B, Bornmann WG, Pellicena P, et al. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res. 2002; 62:4236–4243. PMID: 12154025.
5. Deininger M, Buchdunger E, Druker BJ. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood. 2005; 105:2640–2653. PMID: 15618470.
Article
6. Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006; 355:2408–2417. PMID: 17151364.
7. Hochhaus A, Kreil S, Corbin AS, et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002; 16:2190–2196. PMID: 12399961.
Article
8. Deininger MW, Druker BJ. SRCircumventing imatinib resistance. Cancer Cell. 2004; 6:108–110. PMID: 15324693.
Article
9. Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006; 108:1809–1820. PMID: 16709930.
Article
10. Khan KA, Junaid A, Siddiqui NS, Mukhtar K, Siddiqui S. Imatinib-related bone marrow aplasia after complete cytogenetic response in chronic myeloid leukemia. J Coll Physicians Surg Pak. 2008; 18:176–178. PMID: 18460249.
11. Alabdulaaly A, Rifkind J, Solow H, Messner HA, Lipton JH. Rescue of interferon induced bone marrow aplasia in a patient with chronic myeloid leukemia by allogeneic bone marrow transplant. Leuk Lymphoma. 2004; 45:175–177. PMID: 15061216.
Article
12. Henkes M, van der Kuip H, Aulitzky WE. Therapeutic options for chronic myeloid leukemia: focus on imatinib (Glivec, Gleevectrade mark). Ther Clin Risk Manag. 2008; 4:163–187. PMID: 18728706.
13. Mahon FX, Hayette S, Lagarde V, et al. Evidence that resistance to nilotinib may be due to BCR-ABL, Pgp, or Src kinase overexpression. Cancer Res. 2008; 68:9809–9816. PMID: 19047160.
Article
14. Shukla S, Sauna ZE, Ambudkar SV. Evidence for the interaction of imatinib at the transport-substrate site(s) of the multidrug-resistance-linked ABC drug transporters ABCB1 (P-glycoprotein) and ABCG2. Leukemia. 2008; 22:445–447. PMID: 17690695.
Article
15. Tanabe M, Ieiri I, Nagata N, et al. Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. J Pharmacol Exp Ther. 2001; 297:1137–1143. PMID: 11356939.
16. Gréen H, Söderkvist P, Rosenberg P, Horvath G, Peterson C. mdr-1 single nucleotide polymorphisms in ovarian cancer tissue: G2677T/A correlates with response to paclitaxel chemotherapy. Clin Cancer Res. 2006; 12:854–859. PMID: 16467099.
Article
17. Marzolini C, Paus E, Buclin T, Kim RB. Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther. 2004; 75:13–33. PMID: 14749689.
Article
18. Riva A, Kohane IS. SNPper: retrieval and analysis of human SNPs. Bioinformatics. 2002; 18:1681–1685. PMID: 12490454.
Article
19. Jamroziak K, Robak T. Pharmacogenomics of MDR1/ABCB1 gene: the influence on risk and clinical outcome of haematological malignancies. Hematology. 2004; 9:91–105. PMID: 15203864.
20. Dulucq S, Bouchet S, Turcq B, et al. Multidrug resistance gene (MDR1) polymorphisms are associated with major molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood. 2008; 112:2024–2027. PMID: 18524988.
Article
21. Maffioli M, Camós M, Gaya A, et al. Correlation between genetic polymorphisms of the hOCT1 and MDR1 genes and the response to imatinib in patients newly diagnosed with chronic-phase chronic myeloid leukemia. Leuk Res. 2011; 35:1014–1019. PMID: 21185600.
Article
22. Angelini S, Soverini S, Ravegnini G, et al. Association between imatinib transporters and metabolizing enzymes genotype and response in newly diagnosed chronic myeloid leukemia patients receiving imatinib therapy. Haematologica. 2013; 98:193–200. PMID: 22875622.
Article
23. Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. WHO Classification of tumours. pathology and genetics of tumours of haematopoietic and lymphoid tissues. Lyon, France: IARC Press;2001. p. 20–26.
24. Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009; 27:6041–6051. PMID: 19884523.
Article
25. Ni LN, Li JY, Miao KR, et al. Multidrug resistance gene (MDR1) polymorphisms correlate with imatinib response in chronic myeloid leukemia. Med Oncol. 2011; 28:265–269. PMID: 20204543.
Article
26. Illmer T, Schuler US, Thiede C, et al. MDR1 gene polymorphisms affect therapy outcome in acute myeloid leukemia patients. Cancer Res. 2002; 62:4955–4962. PMID: 12208746.
27. Hoffmeyer S, Burk O, von Richter O, 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 U S A. 2000; 97:3473–3478. PMID: 10716719.
Article
28. Berger U, Maywald O, Pfirrmann M, et al. Gender aspects in chronic myeloid leukemia: long-term results from randomized studies. Leukemia. 2005; 19:984–989. PMID: 15830009.
Article
29. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013; 122:872–884. PMID: 23803709.
30. Mahon FX, Etienne G. Deep molecular response in chronic myeloid leukemia: the new goal of therapy? Clin Cancer Res. 2014; 20:310–322. PMID: 24166905.
Article
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