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Cancer Chemotherapy and Pharmacology

, Volume 79, Issue 4, pp 737–745 | Cite as

hOCT1 gene expression predict for optimal response to Imatinib in Tunisian patients with chronic myeloid leukemia

  • Islem Ben HassineEmail author
  • Hanene Gharbi
  • Ismail Soltani
  • Mouheb Teber
  • Ahlem Farrah
  • Hind Ben Hadj Othman
  • Hassiba Amouri
  • Hatem Bellaaj
  • Rayhane Ben lakhal
  • Neila Ben Romdhane
  • Salem Abbes
  • Samia Menif
Original Article

Abstract

Purpose

Imatinib mesylate (IM) is considered as a highly effective therapy for chronic myeloid leukemia (CML) patients. However, a minority of patients fail to achieve optimal response due to impaired bioavailability of IM. The human organic cation transporter 1 (OCT1; SLC22A1) has been reported to be the main influx transporter involved in IM uptake into CML cells. Genetic variants and/or hOCT1 expression changes may influence IM response. In this study, we aimed to investigate the impact of both hOCT1 polymorphisms located in exon 7 and hOCT1 mRNA levels on the clinical outcome in CML patients.

Methods

hOCT1 expression profile was determined using the quantitative real-time polymerase chain reaction in 69 CML patients treated with IM (35 responders to IM patients and 34 IM-resistant patients), while genotyping of 69 cases and 51 controls for hOCT1 polymorphisms was performed by direct sequencing after amplification of exon7.

Results

Our results showed that the hOCT1 gene was significantly downregulated in the samples of the IM-resistant group when compared with the IM-responder group (p = 0.0211). Moreover, sequencing data show an association in all cases between the SNP 408V>M (g.1222G>A) and an intronic 8 bp (base pairs) insertion of GTAAGTTG (rs36056065) at the 3′ end of exon 7. The genotype and allele distribution of the different SNPs did not differ significantly between the two groups of patients.

Conclusions

hOCT1 mRNA expression may serve as a clinical biomarker of response to imatinib and could be useful to predict IM therapy outcome of CML patients.

Keywords

Chronic myeloid leukemia Imatinib mesylate Resistance hOCT1 Expression Polymorphisms 

Notes

Acknowledgements

We wish to thank all the staff members of the Laboratory of Molecular and Cellular Hematology, Pasteur Institute of Tunis (LR11 IPT07). This work was supported by the Ministry of Higher Education and Scientific Research in Tunisia.

Compliance with ethical standards

Conflict of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

References

  1. 1.
    Leguay T, Mahon F-X (2005) Leucémie myéloïde chronique. EMC Hématologie 2:187–205. doi: 10.1016/j.emch.2005.07.001 CrossRefGoogle Scholar
  2. 2.
    Ren R (2005) Mechanisms of BCR–ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer 5:172–183. doi: 10.1038/nrc1567 CrossRefPubMedGoogle Scholar
  3. 3.
    Apperley JF (2007) Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol 8:1018–1029. doi: 10.1016/S1470-2045(07)70342-X CrossRefPubMedGoogle Scholar
  4. 4.
    Nestal de Moraes G, Souza PS, Costas FC de F et al (2012) The interface between BCR-ABL-dependent and -independent resistance signaling pathways in chronic myeloid leukemia. Leuk Res Treat 2012:1–19. doi: 10.1155/2012/671702 CrossRefGoogle Scholar
  5. 5.
    Eechoute K, Sparreboom A, Burger H et al (2011) Drug transporters and imatinib treatment: implications for clinical practice. Clin Cancer Res 17:406–415. doi: 10.1158/1078-0432.CCR-10-2250 CrossRefPubMedGoogle Scholar
  6. 6.
    Dulucq S, Krajinovic M (2010) The pharmacogenetics of imanitib. Genome Med 2:85.Google Scholar
  7. 7.
    White DL (2006) OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. Blood 108:697–704. doi: 10.1182/blood-2005-11-4687 CrossRefPubMedGoogle Scholar
  8. 8.
    White DL, Saunders VA, Dang P et al (2007) Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity. Blood 110:4064–4072. doi: 10.1182/blood-2007-06-093617 CrossRefPubMedGoogle Scholar
  9. 9.
    Engler JR, Hughes TP, White DL (2011) OCT-1 as a determinant of response to antileukemic treatment. Clin Pharmacol Ther 89:608–611. doi: 10.1038/clpt.2011.12 CrossRefPubMedGoogle Scholar
  10. 10.
    Koepsell H, Endou H (2004) The SLC22 drug transporter family. Pflugers Arch 447:666–676. doi: 10.1007/s00424-003-1089-9 CrossRefPubMedGoogle Scholar
  11. 11.
    Koepsell H, Lips K, Volk C (2007) Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res 24:1227–1251. doi: 10.1007/s11095-007-9254-z CrossRefPubMedGoogle Scholar
  12. 12.
    de Lima LT, Vivona D, Bueno CT et al (2014) Reduced ABCG2 and increased SLC22A1 mRNA expression are associated with imatinib response in chronic myeloid leukemia. Med Oncol. doi: 10.1007/s12032-014-0851-5 PubMedGoogle Scholar
  13. 13.
    Nardinelli L, Sanabani SS, Didone A et al (2012) Pretherapeutic expression of the hOCT1 gene predicts a complete molecular response to imatinib mesylate in chronic-phase chronic myeloid leukemia. Acta Haematol 127:228–234. doi: 10.1159/000336610 CrossRefPubMedGoogle Scholar
  14. 14.
    Gromicho M (2012) Instability of mRNA expression signatures of drug transporters in chronic myeloid leukemia patients resistant to imatinib. Oncol Rep. doi: 10.3892/or.2012.2153 PubMedGoogle Scholar
  15. 15.
    Grinfeld J, Gerrard G, Alikian M et al (2013) A common novel splice variant of SLC22A1 (OCT1) is associated with impaired responses to imatinib in patients with chronic myeloid leukaemia. Br J Haematol 163:631–639. doi: 10.1111/bjh.12591 CrossRefPubMedGoogle Scholar
  16. 16.
    Solali S, Kaviani S, Movassaghpour AA, Aliparasti MR (2013) Real-time polymerase chain reaction testing for quantitative evaluation of hOCT1 and MDR1 expression in patients with chronic myeloid leukemia resistant to imatinib. Lab Med 44:13–19. doi: 10.1309/LMP1ECAE30JSVZEP CrossRefGoogle Scholar
  17. 17.
    Giannoudis A, Wang L, Jorgensen AL et al (2013) The hOCT1 SNPs M420del and M408V alter imatinib uptake and M420del modifies clinical outcome in imatinib-treated chronic myeloid leukemia. Blood 121:628–637. doi: 10.1182/blood-2012-01-405035 CrossRefPubMedGoogle Scholar
  18. 18.
    Baccarani M, Deininger MW, Rosti G et al (2013) European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 122:872–884. doi: 10.1182/blood-2013-05-501569 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Chomzynski P (1987) single-step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction. Anal Biochem 162:156–159. doi: 10.1006/abio.1987.9999 CrossRefGoogle Scholar
  20. 20.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2–∆∆CT method. Methods 25:402–408. doi: 10.1006/meth.2001.1262 CrossRefPubMedGoogle Scholar
  21. 21.
    Chomczynski P (1993) A reagent for the single-step simultaneous isolation of RNA, DNA and proteins from cell and tissue samples. Biotechniques 15(532–534):536–537Google Scholar
  22. 22.
    Ye J, Coulouris G, Zaretskaya I et al (2012) Primer-BLAST: A tool to design target-specific primers for polymerase chain reaction. BMC Bioinform 13:134. doi: 10.1186/1471-2105-13-134 CrossRefGoogle Scholar
  23. 23.
    Yong Y, Lin HE (2005) SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res 15:97–98CrossRefGoogle Scholar
  24. 24.
    Li Z, Zhang Z, He Z et al (2009) A partition-ligation-combination-subdivision EM algorithm for haplotype inference with multiallelic markers: update of the SHEsis http://analysis.bio-x.cn. Cell Res 19:519–523. doi: 10.1038/cr.2009.33
  25. 25.
    Cortes J, Quintás-Cardama A, Kantarjian HM (2011) Monitoring molecular response in chronic myeloid leukemia. Cancer 117:1113–1122. doi: 10.1002/cncr.25527 CrossRefPubMedGoogle Scholar
  26. 26.
    Crossman LC (2005) hOCT 1 and resistance to imatinib. Blood 106:1133–1134. doi: 10.1182/blood-2005-02-0694 CrossRefPubMedGoogle Scholar
  27. 27.
    Thomas J (2004) Active transport of imatinib into and out of cells: implications for drug resistance. Blood 104:3739–3745. doi: 10.1182/blood-2003-12-4276 CrossRefPubMedGoogle Scholar
  28. 28.
    Nies AT, Schaeffeler E, van der Kuip H et al (2014) Cellular uptake of imatinib into leukemic cells is independent of human organic cation transporter 1 (OCT1). Clin Cancer Res Off J Am Assoc. Cancer Res 20:985–994. doi: 10.1158/1078-0432.CCR-13-199929 Google Scholar
  29. 29.
    Hu S, Franke RM, Filipski KK et al (2008) Interaction of Imatinib with Human Organic Ion Carriers. Clin Cancer Res 14:3141–3148. doi: 10.1158/1078-0432.CCR-07-4913 CrossRefPubMedGoogle Scholar
  30. 30.
    Watkins DB, Hughes TP, White DL (2015) OCT1 and imatinib transport in CML: is it clinically relevant? Leukemia 29:1960–1969. doi: 10.1038/leu.2015.170 CrossRefPubMedGoogle Scholar
  31. 31.
    Wang L, Giannoudis A, Lane S et al (2008) Expression of the uptake drug transporter hOCT1 is an important clinical determinant of the response to imatinib in chronic myeloid leukemia. Clin Pharmacol 38 Ther 83:258–264. doi: 10.1038/sj.clpt.6100268 Google Scholar
  32. 32.
    Marin D, Bazeos A, Mahon FX et al (2010) Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 28:2381–2388. doi: 10.1200/JCO.2009.26.3087 CrossRefPubMedGoogle Scholar
  33. 33.
    Razga F, Racil Z, Machova Polakova K et al (2011) The predictive value of human organic cation transporter 1 and ABCB1 expression levels in different cell populations of patients with de novo chronic myelogenous leukemia. Int J Hematol 94:303–306. doi: 10.1007/s12185-011-0924-6 CrossRefPubMedGoogle Scholar
  34. 34.
    Malhotra H, Sharma P, Malhotra B et al (2015) Molecular response to imatinib & its correlation with mRNA expression levels of imatinib influx & efflux transporters in patients with chronic myeloid leukaemia in chronic phase. Indian J Med Res 142:175. doi: 10.4103/0971-5916.164250 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Racil Z, Razga F, Buresova L et al (2010) The assessment of human organic cation transporter 1 (hOCT1) mRNA expression in patients with chronic myelogenous leukemia is affected by the proportion of different cells types in the analyzed cell population. Am J Hematol 85:525–528. doi: 10.1002/ajh.21722 CrossRefPubMedGoogle Scholar
  36. 36.
    Koren-Michowitz M, Buzaglo Z, Ribakovsky E et al (2014) OCT1 genetic variants are associated with long term outcomes in imatinib treated chronic myeloid leukemia patients. Eur J Haematol 92:283–288. doi: 10.1111/ejh.12235 CrossRefPubMedGoogle Scholar
  37. 37.
    Arimany-Nardi C, Koepsell H, Pastor-Anglada M (2015) Role of SLC22A1 polymorphic variants in drug disposition, therapeutic responses, and drug–drug interactions. Pharmacogenomics J 15:473–487CrossRefPubMedGoogle Scholar
  38. 38.
    Vaidya S, Ghosh K, Shanmukhaiah C, Vundinti BR (2015) Genetic variations of hOCT1 gene and CYP3A4/A5 genes and their association with imatinib response in Chronic Myeloid Leukemia. Eur J Pharmacol 765:124–130. doi: 10.1016/j.ejphar.2015.08.034 CrossRefPubMedGoogle Scholar
  39. 39.
    Vine J, Cohen SB, Ruchlemer R et al (2014) Polymorphisms in the human organic cation transporter and the multidrug resistance gene: correlation with imatinib levels and clinical course in patients with chronic myeloid leukemia. Leuk Lymphoma 55:2525–2531. doi: 10.3109/10428194.2014.893307 CrossRefPubMedGoogle Scholar
  40. 40.
    Bazeos A, Marin D, Reid AG et al (2010) hOCT1 transcript levels and single nucleotide polymorphisms as predictive factors for response to imatinib in chronic myeloid leukemia. Leukemia 24:1243–1245. doi: 10.1038/leu.2010.86 CrossRefPubMedGoogle Scholar
  41. 41.
    Takahashi N, Miura M, Scott SA et al (2010) Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia. J Hum Genet 55:731–737. doi: 10.1038/jhg.2010.98 CrossRefPubMedGoogle Scholar
  42. 42.
    Angelini S, Soverini S, Ravegnini G et al (2013) Association between imatinib transporters and metabolizing enzymes genotype and response in newly diagnosed chronic myeloid leukemia patients receiving imatinib therapy. Haematologica 98:193–200. doi: 10.3324/haematol.2012.066480 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Singh O, Chan JY, Lin K et al (2012) SLC22A1-ABCB1 haplotype profiles predict imatinib pharmacokinetics in Asian patients with chronic myeloid leukemia. PLoS One 7:e51771. doi: 10.1371/journal.pone.0051771 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Islem Ben Hassine
    • 1
    • 3
    Email author
  • Hanene Gharbi
    • 1
  • Ismail Soltani
    • 1
  • Mouheb Teber
    • 1
  • Ahlem Farrah
    • 1
  • Hind Ben Hadj Othman
    • 1
  • Hassiba Amouri
    • 1
  • Hatem Bellaaj
    • 2
  • Rayhane Ben lakhal
    • 2
  • Neila Ben Romdhane
    • 2
  • Salem Abbes
    • 1
  • Samia Menif
    • 1
    • 2
  1. 1.Laboratory of Molecular and Cellular Hematology, Pasteur Institute of TunisUniversity of Tunis El ManarTunisTunisia
  2. 2.Faculté de médicine de TunisTunisTunisia
  3. 3.BelvedereTunisia

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