Experimental Hematology
Volume 37, Issue 6 , Pages 692-700 , June 2009

Inhibition of MDR1 does not sensitize primitive chronic myeloid leukemia CD34+ cells to imatinib

  • Sophia Hatziieremia

      Affiliations

    • Drs. Hatziieremia and Jordanides contributed equally to this work.
    • ,
  • Niove E. Jordanides

      Affiliations

    • Drs. Hatziieremia and Jordanides contributed equally to this work.
    • ,
  • Tessa L. Holyoake
    • ,
  • Joanne C. Mountford
    • ,
  • Heather G. Jørgensen

      Affiliations

    • Corresponding Author InformationOffprint requests to: Heather G. Jørgensen, Ph.D., Section of Experimental Haematology, Division of Cancer Sciences and Molecular Pathology, Paul O'Gorman Leukaemia Research Centre, Gartnavel General Hospital, Faculty of Medicine, University of Glasgow, 1053 Great Western Road, Glasgow, G12 0YN, UK

Received 23 December 2008 ,Revised 23 December 2008 ,Accepted 11 February 2009.

References 

  1. 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
  2. Hughes T, Deininger M, Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood. 2006;108:28–37
  3. Roumiantsev S, Shah NP, Gorre ME, et al. Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation of Tyr-253 in the Abl kinase domain P-loop. Proc Natl Acad Sci U S A. 2002;99:10700–10705
  4. Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293:876–880
  5. Swords R, Quinn J, Fay M, O'Donnell R, Goldman J, Murphy PT. CML clonal evolution with resistance to single agent imatinib therapy. Clin Lab Haematol. 2005;27:347–349
  6. Willis SG, Lange T, Demehri S, et al. High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy. Blood. 2005;106:2128–2137
  7. Quintás-Cardama A, Kantarjian H, Cortes J. Targeting ABL and SRC kinases in chronic myeloid leukemia: experience with dasatinib. Future Oncol. 2006;2:655–665
  8. Melo JV, Chuah C. Resistance to imatinib mesylate in chronic myeloid leukaemia. Cancer Lett. 2007;249:121–132
  9. Azam M, Latek RR, Daley GQ. Mechanisms of autoinhibition and STI571/imatinib resistance revealed by mutagenesis of BCR–ABL. Cell. 2003;112:831–843
  10. Corbin AS, La Rosee P, Stoffregen EP, Druker BJ, Deininger MW. Several Bcr-Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib. Blood. 2003;101:4611–4614
  11. Kantarjian H, Talpaz M, O'Brien S, et al. High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood. 2004;103:2873–2878
  12. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354:2531–2541
  13. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354:2542–2551
  14. White DL, Saunders VA, Dang P, et al. 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. 2007;110:4064–4072
  15. White DL, Saunders VA, Dang P, et al. 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. 2006;108:697–704
  16. Hegedus T, Orfi L, Seprodi A, Varadi A, Sarkadi B, Keri G. Interaction of tyrosine kinase inhibitors with the human multidrug transporter proteins, MDR1 and MRP1. Biochim Biophys Acta. 2002;1587:318–325
  17. Shukla S, Sauna ZE, Ambudkar SV. Evidence for the interaction of imatinib at the transport-substrate sites of the multidrug-resistance linked ABC drug transporters ABCB1 (P-glycoprotein) and ABCG2. Leukemia. 2008;22:445–447
  18. Hamada A, Miyano H, Watanabe H, Saito H. Interaction of imatinib mesilate with human P-glycoprotein. J Pharmacol Exp Ther. 2003;307:824–828
  19. Dai H, Marbach P, Lemaire M, Hayes M, Elmquist WF. Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux. J Pharmacol Exp Ther. 2003;304:1085–1092
  20. Hirayama C, Watanabe H, Nakashima R, et al. Constitutive overexpression of P-glycoprotein, rather than breast cancer resistance protein or organic cation transporter 1, contributes to acquisition of imatinib-resistance in K562 Cells. Pharm Res. 2008;25:827–835
  21. llmer T, Schaich M, Platzbecker U, et al. P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate. Leukemia. 2004;18:401–408
  22. Mahon FX, Belloc F, Lagarde V, et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood. 2003;101:2368–2373
  23. Widmer N, Rumpold H, Untergasser G, Fayet A, Buclin T, Decosterd LA. Resistant reversal by RNAi silencing of MDR1 in CML cells associated with increase in imatinib intracellular levels. Leukemia. 2007;21:1561–1562
  24. Rumpold H, Wolf AM, Gruenewald K, Gastl G, Gunsilius E, Wolf D. RNAi-mediated knockdown of P-glycoprotein using a transposon-based vector system durably restores imatinib sensitivity in imatinib-resistant CML cell lines. Exp Hematol. 2005;33:767–775
  25. Ferrao PT, Frost MJ, Siah SP, Ashman LK. Overexpression of P-glycoprotein in K562 cells does not confer resistance to the growth inhibitory effects of imatinib (STI571) in vitro. Blood. 2003;102:4499–4503
  26. Zong Y, Zhou S, Sorrentino BP. Loss of P-glycoprotein expression in hematopoietic stem cells does not improve responses to imatinib in a murine model of chronic myelogenous leukemia. Leukemia. 2005;19:1590–1596
  27. Udomsakdi C, Eaves CJ, Swolin B, Reid DS, Barnett MJ, Eaves AC. Rapid decline of chronic myeloid leukemic cells in long-term culture due to a defect at the leukemic stem cell level. Proc Natl Acad Sci U S A. 1990;89:6192–6196
  28. Holyoake T, Jiang X, Eaves C, Eaves A. Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood. 1999;94:2056–2064
  29. Holyoake TL, Jiang X, Jorgensen HG, et al. Primitive quiescent leukemic cells from patients with chronic myeloid leukemia spontaneously initiate factor-independent growth in vitro in association with up-regulation of expression of interleukin-3. Blood. 2001;97:720–728
  30. Copland M, Hamilton A, Elrick LJ, et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood. 2006;107:4532–4539
  31. Graham SM, Jørgensen HG, Allan E, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002;99:319–325
  32. Larson RA, Druker BJ, Guilhot F, et al. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood. 2008;111:4022–4028
  33. Jordanides NE, Jorgensen HG, Holyoake TL, Mountford JC. Functional ABCG2 is overexpressed on primary CML CD34+ cells and is inhibited by imatinib mesylate. Blood. 2006;108:1370–1373
  34. Noonan KE, Beck C, Holzmayer TA, et al. Quantitative analysis of MDR1 (multidrug resistance) gene expression in human tumors by polymerase chain reaction. Proc Natl Acad Sci U S A. 1990;87:7160–7164
  35. Galimberti S, Guerrini F, Palumbo GA, et al. Evaluation of BCRP and MDR-1 co-expression by quantitative molecular assessment in AML patients. Leuk Res. 2004;28:367–372
  36. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C[T]) method. Methods. 2001;25:402–408
  37. Guetens G, Prenen H, De Boeck G, et al. Simultaneous determination of AMN107 and Imatinib (Gleevec, Glivec, STI571) in cultured tumour cells using an isocratic high-performance liquid chromatography procedure with UV detection. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;846:341–345
  38. Robey RW, Honjo Y, van de Laar A, et al. A functional assay for detection of the mitoxantrone resistance protein, MXR (ABCG2). Biochim Biophys Acta. 2001;1512:171–182
  39. Hamilton A, Elrick L, Myssina S, et al. BCR-ABL activity and its response to drugs can be determined in CD34 + CML stem cells by CrkL phosphorylation status using flow cytometry. Leukemia. 2006;20:1035–1039
  40. Jiang X, Zhao Y, Smith C, et al. Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCR-ABL targeted therapies. Leukemia. 2007;21:926–935
  41. Thomas J, Wang L, Clark RE, Pirmohamed M. Active transport of imatinib into and out of cells: implications for drug resistance. Blood. 2004;104:3739–3745
  42. Stavrovskaya A, Turkina A, Sedyakhina N, et al. Prognostic value of p-glycoprotein and leukocyte differentiation antigens in chronic myeloid leukemia. Leuk Lymphoma. 1998;28:469–482
  43. Carter A, Dann EJ, Katz T, et al. Cells from chronic myelogenous leukaemia patients at presentation exhibit multidrug resistance not mediated by either MDR1 or MRP1. Br J Haematol. 2001;114:581–590
  44. White DL, Saunders VA, Quinn SR, Manley PW, Hughes TP. Imatinib increases the intracellular concentration of nilotinib, which may explain the observed synergy between these drugs. Blood. 2007;109:3609–3610
  45. Houghton PJ, Germain GS, Harwood FC, et al. Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro. Cancer Res. 2004;64:2333–2337
  46. Burger H, van Tol H, Boersma AW, et al. Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump. Blood. 2004;104:2940–2942
  47. Peng B, Hayes M, Resta D, et al. Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients. J Clin Oncol. 2004;22:935–942
  48. Wang L, Giannoudis A, Lane S, Williamson P, Pirmohamed M, Clark RE. Expression of the uptake drug transporter hOCT1 is an important clinical determinant of the response to imatinib in chronic myeloid leukemia. Clin Pharmacol Ther. 2008;83:258–264
  49. Szakács G, Váradi A, Ozvegy-Laczka C, Sarkadi B. The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME-Tox). Drug Discov Today. 2008;13:379–393

PII: S0301-472X(09)00054-X

doi: 10.1016/j.exphem.2009.02.006

Experimental Hematology
Volume 37, Issue 6 , Pages 692-700 , June 2009

Article Tools

* Image Usage & Resolution