Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Chronic myelogenous leukemia

The clinical significance of ABCB1 overexpression in predicting outcome of CML patients undergoing first-line imatinib treatment

Leukemia volume 31, pages 75–82 (2017)Cite this article

Subjects

Abstract

Tyrosine kinase inhibitor (TKI) therapy results in excellent responses in the majority of patients with chronic myeloid leukaemia. First-line imatinib treatment, with selective switching to nilotinib when patients fail to meet specific molecular targets or for imatinib intolerance, results in excellent overall molecular responses and survival. However, this strategy is less effective in cases of primary imatinib resistance; moreover, 25% of patients develop secondary resistance such that 20–35% of patients initially treated with imatinib will eventually experience treatment failure. Early identification of these patients is of high clinical relevance. Since the drug efflux transporter ABCB1 has previously been implicated in TKI resistance, we determined if early increases in ABCB1 mRNA expression (fold change from diagnosis to day 22 of imatinib therapy) predict for patient response. Indeed, patients exhibiting a high fold rise (⩾2.2, n=79) were significantly less likely to achieve early molecular response (BCR-ABL1IS ⩽10% at 3 months; P=0.001), major molecular response (P<0.0001) and MR4.5 (P<0.0001). Additionally, patients demonstrated increased levels of ABCB1 mRNA before the development of mutations and/or progression to blast crisis. Patients with high fold rise in ABCB1 mRNA were also less likely to achieve major molecular response when switched to nilotinib therapy (49% vs 82% of patients with low fold rise). We conclude that early evaluation of the fold change in ABCB1 mRNA expression may identify patients likely to be resistant to first- and second-generation TKIs and who may be candidates for alternative therapy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Nowell PC, Hungerford DA . A minute chromosome in human chronic granulocytic leukemia. Science 1960; 132: 1497.

    Google Scholar 

  2. Rowley JD . Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973; 243: 290–293.

    Article  CAS  PubMed  Google Scholar 

  3. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996; 2: 561–566.

    Article  CAS  PubMed  Google Scholar 

  4. Giles FJ, le Coutre PD, Pinilla-Ibarz J, Larson RA, Gattermann N, Ottmann OG et al. Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study. Leukemia 2013; 27: 107–112.

    Article  CAS  PubMed  Google Scholar 

  5. Khorashad JS, Kelley TW, Szankasi P, Mason CC, Soverini S, Adrian LT et al. BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML: frequency and clonal relationships. Blood 2013; 121: 489–498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Deininger M, O'Brien SG, Guilhot F, Goldman JM, Hochhaus A, Hughes TP et al. International Randomized Study of Interferon vs STI571 (IRIS) 8-Year Follow Up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. ASH Annu Meet Abstr 2009; 114: 1126.

    Google Scholar 

  7. Hochhaus A, Saglio G, Larson RA, Kim DW, Etienne G, Rosti G et al. Nilotinib is associated with a reduced incidence of BCR-ABL mutations vs imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Blood 2013; 121: 3703–3708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2010; 362: 2260–2270.

    Article  CAS  PubMed  Google Scholar 

  9. Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010; 362: 2251–2259.

    Article  CAS  PubMed  Google Scholar 

  10. Branford S, Rudzki Z, Walsh S, Parkinson I, Grigg A, Szer J et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood 2003; 102: 276–283.

    Article  CAS  PubMed  Google Scholar 

  11. Hughes T, Saglio G, Branford S, Soverini S, Kim DW, Muller MC et al. Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol 2009; 27: 4204–4210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jabbour E, Kantarjian H, Jones D, Talpaz M, Bekele N, O'Brien S et al. Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia 2006; 20: 1767–1773.

    Article  CAS  PubMed  Google Scholar 

  13. Muller MC, Cortes JE, Kim DW, Druker BJ, Erben P, Pasquini R et al. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood 2009; 114: 4944–4953.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Barnes DJ, Palaiologou D, Panousopoulou E, Schultheis B, Yong AS, Wong A et al. Bcr-Abl expression levels determine the rate of development of resistance to imatinib mesylate in chronic myeloid leukemia. Cancer Res 2005; 65: 8912–8919.

    Article  CAS  PubMed  Google Scholar 

  15. Campbell LJ, Patsouris C, Rayeroux KC, Somana K, Januszewicz EH, Szer J . BCR/ABL amplification in chronic myelocytic leukemia blast crisis following imatinib mesylate administration. Cancer Genet Cytogenet 2002; 139: 30–33.

    Article  CAS  PubMed  Google Scholar 

  16. De Braekeleer E, Douet-Guilbert N, Le Bris MJ, Morel F, De Braekeleer M . Translocation 3;21, trisomy 8, and duplication of the Philadelphia chromosome: a rare but recurrent cytogenetic pathway in the blastic phase of chronic myeloid leukemia. Cancer Genet Cytogenet 2007; 179: 159–161.

    Article  CAS  PubMed  Google Scholar 

  17. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001; 293: 876–880.

    Article  CAS  PubMed  Google Scholar 

  18. Hochhaus A, Kreil S, Corbin AS, La Rosee P, Muller MC, Lahaye T et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 2002; 16: 2190–2196.

    Article  CAS  PubMed  Google Scholar 

  19. Donato NJ, Wu JY, Stapley J, Gallick G, Lin H, Arlinghaus R et al. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood 2003; 101: 690–698.

    Article  CAS  PubMed  Google Scholar 

  20. Hayette S, Chabane K, Michallet M, Michallat E, Cony-Makhoul P, Salesse S et al. Longitudinal studies of SRC family kinases in imatinib- and dasatinib-resistant chronic myelogenous leukemia patients. Leuk Res 2011; 35: 38–43.

    Article  CAS  PubMed  Google Scholar 

  21. Mahon FX, Hayette S, Lagarde V, Belloc F, Turcq B, Nicolini F et al. Evidence that resistance to nilotinib may be due to BCR-ABL, Pgp, or Src kinase overexpression. Cancer Res 2008; 68: 9809–9816.

    Article  CAS  PubMed  Google Scholar 

  22. Wu J, Meng F, Kong LY, Peng Z, Ying Y, Bornmann WG et al. Association between imatinib-resistant BCR-ABL mutation-negative leukemia and persistent activation of LYN kinase. J Natl Cancer Inst 2008; 100: 926–939.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wu J, Meng F, Lu H, Kong L, Bornmann W, Peng Z et al. Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl protein stability in imatinib-resistant chronic myelogenous leukemia cells. Blood 2008; 111: 3821–3829.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Crossman LC, Druker BJ, Deininger MW, Pirmohamed M, Wang L, Clark RE . hOCT 1 and resistance to imatinib. Blood 2005; 106: 1133–1134; author reply 1134.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  CAS  PubMed  Google Scholar 

  26. White DL, Dang P, Engler J, Frede A, Zrim S, Osborn M et al. Functional activity of the OCT-1 protein is predictive of long-term outcome in patients with chronic-phase chronic myeloid leukemia treated with imatinib. J Clin Oncol 2010; 28: 2761–2767.

    Article  CAS  PubMed  Google Scholar 

  27. White DL, Radich J, Soverini S, Saunders VA, Frede A, Dang P et al. Chronic phase chronic myeloid leukemia patients with low OCT-1 activity randomised to high-dose imatinib achieve better responses, and lower failure rates, than those randomized to standard-dose. Haematologica 2012; 97: 907–914.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. White DL, Saunders VA, Dang P, Engler J, Venables A, Zrim S 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.

    Article  CAS  PubMed  Google Scholar 

  29. White DL, Saunders VA, Dang P, Engler J, Zannettino AC, Cambareri AC 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.

    Article  CAS  PubMed  Google Scholar 

  30. Hiwase DK, Saunders V, Hewett D, Frede A, Zrim S, Dang P et al. Dasatinib cellular uptake and efflux in chronic myeloid leukemia cells: therapeutic implications. Clin Cancer Res 2008; 14: 3881–3888.

    Article  CAS  PubMed  Google Scholar 

  31. Eadie LN, Hughes TP, White DL . Interaction of the efflux transporters ABCB1 and ABCG2 with imatinib, nilotinib, and dasatinib. Clin Pharmacol Ther 2014; 95: 294–306.

    Article  CAS  PubMed  Google Scholar 

  32. Burger H, van Tol H, Brok M, Wiemer EA, de Bruijn EA, Guetens G et al. Chronic imatinib mesylate exposure leads to reduced intracellular drug accumulation by induction of the ABCG2 (BCRP) and ABCB1 (MDR1) drug transport pumps. Cancer Biol Ther 2005; 4: 747–752.

    Article  CAS  PubMed  Google Scholar 

  33. Gromicho M, Dinis J, Magalhaes M, Fernandes AR, Tavares P, Laires A et al. Development of imatinib and dasatinib resistance: dynamics of expression of drug transporters ABCB1, ABCC1, ABCG2, MVP, and SLC22A1. Leuk Lymphoma 2011; 52: 1980–1990.

    Article  CAS  PubMed  Google Scholar 

  34. Hirayama C, Watanabe H, Nakashima R, Nanbu T, Hamada A, Kuniyasu A 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.

    Article  CAS  PubMed  Google Scholar 

  35. Illmer T, Schaich M, Platzbecker U, Freiberg-Richter J, Oelschlagel U, von Bonin M 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.

    Article  CAS  PubMed  Google Scholar 

  36. Mahon FX, Belloc F, Lagarde V, Chollet C, Moreau-Gaudry F, Reiffers J et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood 2003; 101: 2368–2373.

    Article  CAS  PubMed  Google Scholar 

  37. Mahon FX, Deininger MW, Schultheis B, Chabrol J, Reiffers J, Goldman JM et al. Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood 2000; 96: 1070–1079.

    CAS  PubMed  Google Scholar 

  38. Tang C, Schafranek L, Watkins DB, Parker WT, Moore S, Prime JA et al. Tyrosine kinase inhibitor resistance in chronic myeloid leukemia cell lines: investigating resistance pathways. Leuk Lymphoma 2011; 52: 2139–2147.

    Article  CAS  PubMed  Google Scholar 

  39. Widmer N, Colombo S, Buclin T, Decosterd LA . Functional consequence of MDR1 expression on imatinib intracellular concentrations. Blood 2003; 102: 1142.

    Article  CAS  PubMed  Google Scholar 

  40. White D, Saunders V, Grigg A, Arthur C, Filshie R, Leahy MF et al. Measurement of in vivo BCR-ABL kinase inhibition to monitor imatinib-induced target blockade and predict response in chronic myeloid leukemia. J Clin Oncol 2007; 25: 4445–4451.

    Article  CAS  PubMed  Google Scholar 

  41. White D, Saunders V, Lyons AB, Branford S, Grigg A, To LB et al. In vitro sensitivity to imatinib-induced inhibition of ABL kinase activity is predictive of molecular response in patients with de novo CML. Blood 2005; 106: 2520–2526.

    Article  CAS  PubMed  Google Scholar 

  42. Eadie LN, Saunders VA, Hughes TP, White DL . Degree of kinase inhibition achieved in vitro by imatinib and nilotinib is decreased by high levels of ABCB1 but not ABCG2. Leuk Lymphoma 2013; 54: 569–578.

    Article  CAS  PubMed  Google Scholar 

  43. Yeung DT, Osborn MP, White DL, Branford S, Braley J, Herschtal A et al. TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood 2015; 125: 915–923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chomczynski P, Sacchi N . Single-step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction. Anal Biochem 1987; 162: 156–159.

    Article  CAS  PubMed  Google Scholar 

  45. Branford S, Fletcher L, Cross NC, Muller MC, Hochhaus A, Kim DW et al. Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials. Blood 2008; 112: 3330–3338.

    Article  CAS  PubMed  Google Scholar 

  46. Cross NC, Hughes TP, Hochhaus A, Goldman JM . International standardisation of quantitative real-time RT-PCR for BCR-ABL. Leuk Res 2008; 32: 505–506.

    Article  CAS  PubMed  Google Scholar 

  47. Branford S, Hughes TP, Rudzki Z . Monitoring chronic myeloid leukaemia therapy by real-time quantitative PCR in blood is a reliable alternative to bone marrow cytogenetics. Br J Haematol 1999; 107: 587–599.

    Article  CAS  PubMed  Google Scholar 

  48. Agrawal M, Hanfstein B, Erben P, Wolf D, Ernst T, Fabarius A et al. MDR1 expression predicts outcome of Ph+ chronic phase CML patients on second-line nilotinib therapy after imatinib failure. Leukemia 2014; 28: 1478–1485.

    Article  CAS  PubMed  Google Scholar 

  49. Giannoudis A, Davies A, Harris RJ, Lucas CM, Pirmohamed M, Clark RE . The clinical significance of ABCC3 as an imatinib transporter in chronic myeloid leukaemia. Leukemia 2014; 28: 1360–1363.

    Article  CAS  PubMed  Google Scholar 

  50. Kim YK, Lee SS, Jeong SH, Ahn JS, Yang DH, Lee JJ et al. OCT-1, ABCB1, and ABCG2 expression in imatinib-resistant chronic myeloid leukemia treated with dasatinib or nilotinib. Chonnam Med J 2014; 50: 102–111.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Branford S, Yeung DT, Parker WT, Roberts ND, Purins L, Braley JA et al. Prognosis for patients with CML and &gt;10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline. Blood 2014; 124: 511–518.

    Article  CAS  PubMed  Google Scholar 

  52. Larson RA, Druker BJ, Guilhot F, O'Brien SG, Riviere GJ, Krahnke T 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.

    Article  CAS  PubMed  Google Scholar 

  53. Picard S, Titier K, Etienne G, Teilhet E, Ducint D, Bernard MA et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2007; 109: 3496–3499.

    Article  CAS  PubMed  Google Scholar 

  54. White D, Dang P, Venables A, Saunders V, Zrim S, Zannettino A et al. ABCB1 overexpression may predispose imatinib treated CML patients to the development of Abl kinase domain mutations, and may be an important contributor to acquired resistance. ASH Annu Meet Abstr 2006; 108: 2144.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia

    L N Eadie, P Dang, V A Saunders, D T Yeung, T P Hughes & D L White

  2. Department of Medicine, University of Adelaide, Adelaide, SA, Australia

    L N Eadie, D T Yeung, T P Hughes & D L White

  3. Haematology Department, SA Pathology, Adelaide, SA, Australia

    D T Yeung, M P Osborn & T P Hughes

  4. Oncology Department, Women’s and Children Hospital, Adelaide, SA, Australia

    M P Osborn

  5. Clinical Haematology, Austin Health, Heidelberg, VIC, Australia

    A P Grigg

  6. Centre for Cancer Biology, Adelaide, SA, Australia

    T P Hughes

  7. Australasian Leukaemia and Lymphoma Group, Melbourne, VIC, Australia

    T P Hughes

  8. Department of Paediatrics, University of Adelaide, Adelaide, SA, Australia

    D L White

Authors
  1. L N Eadie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P Dang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V A Saunders
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D T Yeung
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M P Osborn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A P Grigg
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T P Hughes
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D L White
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D L White.

Ethics declarations

Competing interests

LNE, PD, VAS, MPO and APG have no conflict of interest to declare. DTY, TPH and DLW receive honoraria and research funds from Novartis Pharmaceuticals, and are members of Advisory Boards for Novartis. DTY and TPH are chairs of the CML/MPN disease group for the Australasian Leukaemia and Lymphoma Group (ALLG). Neither Novartis nor ALLG had roles in the design of the study, collection and analysis of the data or the decision to publish.

Additional information

Author contributions

LNE designed the experiments, performed the experiments, analysed the data, wrote the manuscript and created the figures. PD performed the experiments and reviewed the manuscript. VAS coordinated patient samples and reviewed the manuscript. DTY and MPO supervised conduct of TIDEL II, contributed patients and reviewed the manuscript. APG designed TIDEL II, supervised conduct of TIDEL II, contributed patients, served on the TIDEL II management committee and reviewed the paper. TPH designed the experiments, designed TIDEL II, supervised conduct of TIDEL II, contributed patients, served on the TIDEL II management committee and reviewed the paper. DLW designed the experiments, analysed the data, created the figures and reviewed the manuscript.

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Eadie, L., Dang, P., Saunders, V. et al. The clinical significance of ABCB1 overexpression in predicting outcome of CML patients undergoing first-line imatinib treatment. Leukemia 31, 75–82 (2017). https://doi.org/10.1038/leu.2016.179

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2016.179

This article is cited by

Search

Advanced search

Quick links