Molecular Diagnosis & Therapy

, Volume 20, Issue 4, pp 315–333 | Cite as

Chronic Myeloid Leukemia in the Era of Tyrosine Kinase Inhibitors: An Evolving Paradigm of Molecularly Targeted Therapy

  • Mohamed A. M. Ali
Review Article


Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, characterized by the unrestrained expansion of pluripotent hematopoietic stem cells. CML was the first malignancy in which a unique chromosomal abnormality was identified and a pathophysiologic association was suggested. The hallmark of CML is a reciprocal chromosomal translocation between the long arms of chromosomes 9 and 22, t(9; 22)(q34; q11), creating a derivative 9q+ and a shortened 22q–. The latter, known as the Philadelphia (Ph) chromosome, harbors the breakpoint cluster region-abelson (BCR-ABL) fusion gene, encoding the constitutively active BCR-ABL tyrosine kinase that is necessary and sufficient for initiating CML. The successful implementation of tyrosine kinase inhibitors (TKIs) for the treatment of CML remains a flagship for molecularly targeted therapy in cancer. TKIs have changed the clinical course of CML; however, some patients nonetheless demonstrate primary or secondary resistance to such therapy and require an alternative therapeutic strategy. Therefore, the assessment of early response to treatment with TKIs has become an important tool in the clinical monitoring of CML patients. Although mutations in the BCR-ABL have proven to be the most prominent mechanism of resistance to TKIs, other mechanisms—either rendering the leukemic cells still dependent on BCR-ABL activity or supporting oncogenic properties of the leukemic cells independent of BCR-ABL signaling—have been identified. This article provides an overview of the current understanding of CML pathogenesis; recommendations for diagnostic tools, treatment strategies, and management guidelines; and highlights the BCR-ABL-dependent and -independent mechanisms that contribute to the development of resistance to TKIs.


Imatinib Chronic Myeloid Leukemia Dasatinib Nilotinib Chronic Myeloid Leukemia Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Compliance with Ethical Standards

Conflict of interest

Mohamed A.M. Ali has no conflicts of interest directly relevant to the content of this article.


No sources of funding were used to conduct this study or prepare this manuscript.


  1. 1.
    Apperley JF. Chronic myeloid leukaemia. Lancet. 2015;385(9976):1447–59.PubMedCrossRefGoogle Scholar
  2. 2.
    Chereda B, Melo JV. Natural course and biology of CML. Ann. Hematol. 2015;94(Suppl 2):S107–21.PubMedCrossRefGoogle Scholar
  3. 3.
    Hochhaus A, Ernst T, Eigendorff E, La Rosée P. Causes of resistance and treatment choices of second- and third-line treatment in chronic myelogenousleukemia patients. Ann. Hematol. 2015;94(Suppl 2):S133–40.PubMedCrossRefGoogle Scholar
  4. 4.
    Baccarani M, Castagnetti F, Gugliotta G, Rosti G. A review of the European LeukemiaNet recommendations for the management of CML. Ann. Hematol. 2015;94(Suppl 2):S141–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Balabanov S, Braig M, Brümmendorf TH. Current aspects in resistance against tyrosine kinase inhibitors in chronic myelogenous leukemia. Drug Discov Today Technol. 2014;11:89–99.PubMedCrossRefGoogle Scholar
  6. 6.
    Melo JV, Hughes TP, Apperley JF. Chronic Myeloid Leukemia. American Society of Hematology Education Program. Hematology. 2003;2003:132–52.CrossRefGoogle Scholar
  7. 7.
    Rowley JD. Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973;243(5405):290–3.PubMedCrossRefGoogle Scholar
  8. 8.
    Nowell PC, Hungerford DA. A minute chromosome in human granulocytic leukemia. Science. 1960;142:1497.Google Scholar
  9. 9.
    Shtivelman E, Lifshitz B, Gale RP, Canaani E. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature. 1985;315(6020):550–4.PubMedCrossRefGoogle Scholar
  10. 10.
    Lugo TG, Pendergast AM, Muller AJ, Witte ON. Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science. 1990;247(4946):1079–82.PubMedCrossRefGoogle Scholar
  11. 11.
    Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 1990;247(4944):824–30.PubMedCrossRefGoogle Scholar
  12. 12.
    Rodriguez-Abreu D, Bordoni A, Zucca E. Epidemiology of hematological malignancies. Ann. Oncol. 2007;18(Suppl 1):i3–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Quintás-Cardama A, Cortes JE. Chronic myeloid leukemia: diagnosis and treatment. Mayo Clin. Proc. 2006;81:973–88.PubMedCrossRefGoogle Scholar
  14. 14.
    Deininger MW, Goldman JM, Melo JV. The molecular biology of chronic myeloid leukemia. Blood. 2000;96(10):3343–56.PubMedGoogle Scholar
  15. 15.
    Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, Cervantes F, Clark RE, Cortes JE, Guilhot F, Hjorth-Hansen H, Hughes TP, Kantarjian HM, Kim DW, Larson RA, Lipton JH, Mahon FX, Martinelli G, Mayer J, Müller MC, Niederwieser D, Pane F, Radich JP, Rousselot P, Saglio G, Saußele S, Schiffer C, Silver R, Simonsson B, Steegmann JL, Goldman JM, Hehlmann R. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872–84.PubMedCrossRefGoogle Scholar
  16. 16.
    Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2012 update on diagnosis, monitoring, and management. Am. J. Hematol. 2012;87(11):1037–45.PubMedCrossRefGoogle Scholar
  17. 17.
    Quintás-Cardama A, Cortes J. Molecular biology of bcr-abl1- positive chronic myeloid leukemia. Blood. 2009;113(8):1619–30.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Hantschel O, Superti-Furga G. Regulation of the c-Abl and Bcr-Abl tyrosine kinases. Nat. Rev. Mol. Cell Biol. 2004;5(1):33–44.PubMedCrossRefGoogle Scholar
  19. 19.
    Kurzrock R, Kantarjian HM, Druker BJ, Talpaz M. Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics. Ann. Intern. Med. 2003;138(10):819–30.PubMedCrossRefGoogle Scholar
  20. 20.
    Pluk H, Dorey K, Superti-Furga G. Autoinhibition of c-Abl. Cell. 2002;108(2):247–59.PubMedCrossRefGoogle Scholar
  21. 21.
    Ren R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat. Rev. Cancer. 2005;5(3):172–83.PubMedCrossRefGoogle Scholar
  22. 22.
    Cheng K, Kurzrock R, Qiu X, Estrov Z, Ku S, Dulski KM, Wang JY, Talpaz M. Reduced focal adhesion kinase and paxillin phosphorylation in BCR-ABL-transfected cells. Cancer. 2002;95(2):440–50.PubMedCrossRefGoogle Scholar
  23. 23.
    Cilloni D, Saglio G. Molecular pathways: BCR-ABL. Clin. Cancer Res. 2012;18(4):930–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Puil L, Liu J, Gish G, Mbamalu G, Bowtell D, Pelicci PG, Arlinghaus R, Pawson T. Bcr-Abl oncoproteins bind directly to activators of the Ras signalling pathway. EMBO J. 1994;13(4):764–73.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Xie S, Wang Y, Liu J, Sun T, Wilson MB, Smithgall TE, Arlinghaus RB. Involvement of Jak2 tyrosine phosphorylation in Bcr-Abl transformation. Oncogene. 2001;20(43):6188–95.PubMedCrossRefGoogle Scholar
  26. 26.
    Carlesso N, Frank DA, Griffin JD. Tyrosyl phosphorylation and DNA binding activity of signal transducers and activators of transcription (STAT) proteins in hematopoietic cell lines transformed by Bcr/Abl. J. Exp. Med. 1996;183(3):811–20.PubMedCrossRefGoogle Scholar
  27. 27.
    Skorski T, Kanakaraj P, Nieborowska-Skorska M, Ratajczak MZ, Wen SC, Zon G, Gewirtz AM, Perussia B, Calabretta B. Phosphatidylinositol-3 kinase activity is regulated by BCR/ABL and is required for the growth of Philadelphia chromosome-positive cells. Blood. 1995;86(2):726–36.PubMedGoogle Scholar
  28. 28.
    Notari M, Neviani P, Santhanam R, Blaser BW, Chang JS, Galietta A, Willis AE, Roy DC, Caligiuri MA, Marcucci G, Perrotti D. A MAPK/HNRPK pathway controls BCR-ABL oncogenic potential by regulating MYC mRNA translation. Blood. 2006;107(6):2507–16.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Neshat MS, Raitano AB, Wang HG, Reed JC, Sawyers CL. The survival function of the Bcr-Abl oncogene is mediated by Bad-dependent and -independent pathways: roles for phosphatidyl inositol 3-kinase and Raf. Mol. Cell. Biol. 2000;20(4):1179–86.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Gesbert F, Griffin JD. Bcr/Abl activates transcription of the Bcl-X gene through STAT5. Blood. 2000;96(6):2269–76.PubMedGoogle Scholar
  31. 31.
    Hao SX, Ren R. Expression of interferon consensus sequence binding protein (ICSBP) is downregulated in Bcr-Abl-induced murine chronic myeloid leukemia-like disease, and forced co-expression of ICSBP inhibits Bcr-Abl-induced myeloproliferative disorder. Mol. Cell. Biol. 2000;20(4):1149–61.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Middleton MK, Zukas AM, Rubinstein T, Jacob M, Zhu P, Zhao L, Blair I, Puré E. Identification of 12/15-lipoxygenase as a suppressor of myeloproliferative disease. J. Exp. Med. 2006;203(11):2529–40.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Eiring AM, Deininger MW. Individualizing kinase-targeted cancer therapy: the paradigm of chronic myeloid leukemia. Genome Biol. 2014;15(9):461.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Reddy EP, Aggarwal AK. The ins and outs of bcr-abl inhibition. Genes Cancer. 2012;3(5–6):447–54.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Druker BJ, Lydon NB. Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myeloid leukemia. J Clin Invest. 2000;105(1):3–7.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Deininger M, Buchdunger E, Druker BJ. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood. 2005;105(7):2640–53.PubMedCrossRefGoogle Scholar
  37. 37.
    Hantschel O, Rix U, Superti-Furga G. Target spectrum of the BCR-ABL inhibitors imatinib, nilotinib and dasatinib. Leuk. Lymphoma. 2008;49(4):615–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Liu Y, Gray NS. Rational design of inhibitors that bind to inactive kinase conformations. Nat. Chem. Biol. 2006;2(7):358–64.PubMedCrossRefGoogle Scholar
  39. 39.
    Modugno M. New resistance mechanisms for small kinase inhibitors of Abl kinase. Drug Discov Today Technol. 2014;11:5–10.PubMedCrossRefGoogle Scholar
  40. 40.
    Zuccotto F, Ardini E, Casale E, Angiolini M. Through the “gatekeeper door”: exploiting the active kinase conformation. J. Med. Chem. 2010;53(7):2681–94.PubMedCrossRefGoogle Scholar
  41. 41.
    O’Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, Adrian LT, Zhou T, Huang WS, Xu Q, Metcalf CA 3rd, Tyner JW, Loriaux MM, Corbin AS, Wardwell S, Ning Y, Keats JA, Wang Y, Sundaramoorthi R, Thomas M, Zhou D, Snodgrass J, Commodore L, Sawyer TK, Dalgarno DC, Deininger MW, Druker BJ, Clackson T. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation- based resistance. Cancer Cell. 2009;16(5):401–12.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, O’Hare T, Hu S, Narasimhan NI, Rivera VM, Clackson T, Turner CD, Haluska FG, Druker BJ, Deininger MW, Talpaz M. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N. Engl. J. Med. 2012;367(22):2075–88.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Hochhaus A, Hughes T. Clinical resistance to imatinib: mechanisms and implications. Hematol Oncol Clin N Am. 2004;18(3):641–56.CrossRefGoogle Scholar
  44. 44.
    Donato NJ, Wu JY, Stapley J, Lin H, Arlinghaus R, Aggarwal BB, Shishodia S, Albitar M, Hayes K, Kantarjian H, Talpaz M. Imatinib mesylate resistance through BCR-ABL independence in chronic myeloid leukemia. Cancer Res. 2004;64(2):672–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Diamond JM, Melo JV. Mechanisms of resistance to BCR-ABL kinase inhibitors. Leuk. Lymphoma. 2011;52(Suppl 1):12–22.PubMedCrossRefGoogle Scholar
  46. 46.
    Soverini S, Martinelli G, Rosti G, Bassi S, Amabile M, Poerio A, Giannini B, Trabacchi E, Castagnetti F, Testoni N, Luatti S, de Vivo A, Cilloni D, Izzo B, Fava M, Abruzzese E, Alberti D, Pane F, Saglio G, Baccarani M. ABL mutations in late chronic phase chronic myeloid leukemia patients with upfront cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J. Clin. Oncol. 2005;23(18):4100–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293(5531):876–80.PubMedCrossRefGoogle Scholar
  48. 48.
    Jabbour E, Kantarjian H, Jones D, Talpaz M, Bekele N, O’Brien S, Zhou X, Luthra R, Garcia-Manero G, Giles F, Rios MB, Verstovsek S, Cortes J. Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia. 2006;20(10):1767–73.PubMedCrossRefGoogle Scholar
  49. 49.
    Shah NP, Skaggs BJ, Branford S, Hughes TP, Nicoll JM, Paquette RL, Sawyers CL. Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency. J Clin Invest. 2007;117(9):2562–9.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Khorashad JS, Kelley TW, Szankasi P, Mason CC, Soverini S, Adrian LT, Eide CA, Zabriskie MS, Lange T, Estrada JC, Pomicter AD, Eiring AM, Kraft IL, Anderson DJ, Gu Z, Alikian M, Reid AG, Foroni L, Marin D, Druker BJ, O’Hare T, Deininger MW. BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML: frequency and clonal relationships. Blood. 2013;121(3):489–98.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Soverini S, Gnani A, Colarossi S, Castagnetti F, Abruzzese E, Paolini S, Merante S, Orlandi E, de Matteis S, Gozzini A, Iacobucci I, Palandri F, Gugliotta G, Papayannidis C, Poerio A, Amabile M, Cilloni D, Rosti G, Baccarani M, Martinelli G. Philadelphia-positive patients who already harbor imatinib- resistant Bcr-Abl kinase domain mutations have a higher likelihood of developing additional mutations associated with resistance to second- or third-line tyrosine kinase inhibitors. Blood. 2009;114(10):2168–71.PubMedCrossRefGoogle Scholar
  52. 52.
    Hughes T, Saglio G, Branford S, Soverini S, Kim DW, Müller MC, Martinelli G, Cortes J, Beppu L, Gottardi E, Kim D, Erben P, Shou Y, Haque A, Gallagher N, Radich J, Hochhaus A. Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J. Clin. Oncol. 2009;27(25):4204–10.PubMedCrossRefGoogle Scholar
  53. 53.
    Zabriskie MS, Eide CA, Tantravahi SK, Vellore NA, Estrada J, Nicolini FE, Khoury HJ, Larson RA, Konopleva M, Cortes JE, Kantarjian H, Jabbour EJ, Kornblau SM, Lipton JH, Rea D, Stenke L, Barbany G, Lange T, Hernández-Boluda JC, Ossenkoppele GJ, Press RD, Chuah C, Goldberg SL, Wetzler M, Mahon FX, Etienne G, Baccarani M, Soverini S, Rosti G, Rousselot P, Friedman R, Deininger M, Reynolds KR, Heaton WL, Eiring AM, Pomicter AD, Khorashad JS, Kelley TW, Baron R, Druker BJ, Deininger MW, O’Hare T. BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia. Cancer Cell. 2014;26(3):428–42.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Soverini S, de Benedittis C, Mancini M, Martinelli G. Mutations in the BCR-ABL1 kinase domain and elsewhere in chronic myeloid leukemia. Clin. Lymphoma Myeloma Leuk. 2015;15(Suppl):S120–8.PubMedCrossRefGoogle Scholar
  55. 55.
    le Coutre P, Tassi E, Varella-Garcia M, Barni R, Mologni L, Cabrita G, Marchesi E, Supino R, Gambacorti-Passerini C. Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. Blood. 2000;95(5):1758–66.PubMedGoogle Scholar
  56. 56.
    Eechoute K, Sparreboom A, Burger H, Franke RM, Schiavon G, Verweij J, Loos WJ, Wiemer EA, Mathijssen RH. Drug transporters and imatinib treatment: implications for clinical practice. Clin. Cancer Res. 2011;17(3):406–15.PubMedCrossRefGoogle Scholar
  57. 57.
    Clark RE, Knight K, Lucas CM, Pirmohamed M, Wang L. Expression of the imatinib drug transporters h-OCT1 and MDR1 levels determines imatinib response and development of BCR-ABL kinase mutations in chronic myeloid leukemia (CML). Exp. Hematol. 2005;33(7):51–2.Google Scholar
  58. 58.
    Thomas J, Wang L, Clark RE, Pirmohamed M. Active transport of imatinib into and out of cells: implications for drug resistance. Blood. 2004;104(12):3739–45.PubMedCrossRefGoogle Scholar
  59. 59.
    Crossman LC, Druker BJ, Deininger MW, Pirmohamed M, Wang L, Clark RE. hOCT 1 and resistance to imatinib. Blood. 2005;106(3):1133–4.PubMedCrossRefGoogle Scholar
  60. 60.
    Nardinelli L, Sanabani SS, Didone A, Ferreira Pde B, Serpa M, Novaes MM, Marchiani M, Ruiz AL, Lima IS, Chamone Dde A, Bendit I. Pretherapeutic expression of the hOCT1 gene predicts a complete molecular response to imatinib mesylate in chronic-phase chronic 562 myeloid leukemia. Acta Haematol. 2012;127(4):228–34.PubMedCrossRefGoogle Scholar
  61. 61.
    White DL, Saunders VA, Dang P, Engler J, Venables A, Zrim S, Zannettino A, Lynch K, Manley PW, Hughes T. 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(12):4064–72.PubMedCrossRefGoogle Scholar
  62. 62.
    White DL, Dang P, Engler J, Frede A, Zrim S, Osborn M, Saunders VA, Manley PW, Hughes TP. 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(16):2761–7.PubMedCrossRefGoogle Scholar
  63. 63.
    Angelini S, Soverini S, Ravegnini G, Barnett M, Turrini E, Thornquist M, Pane F, Hughes TP, White DL, Radich J, Kim DW, Saglio G, Cilloni D, Iacobucci I, Perini G, Woodman R, Cantelli-Forti G, Baccarani M, Hrelia P, Martinelli G. Association between imatinib transporters and metabolizing enzymes genotype and response in newly diagnosed chronic myeloid leukemia patients receiving imatinib therapy. Haematologica. 2013;98(2):193–200.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Giannoudis A, Wang L, Jorgensen AL, Xinarianos G, Davies A, Pushpakom S, Liloglou T, Zhang JE, Austin G, Holyoake TL, Foroni L, Kottaridis PD, Müller MC, Pirmohamed M, Clark RE. The hOCT1 SNPs M420del and M408V alter imatinib uptake and M420del modifies clinical outcome in imatinib-treated chronic myeloid leukemia. Blood. 2013;121(4):628–37.PubMedCrossRefGoogle Scholar
  65. 65.
    Koren-Michowitz M, Buzaglo Z, Ribakovsky E, Schwarz M, Pessach I, Shimoni A, Beider K, Amariglio N, le Coutre P, Nagler A. OCT1 genetic variants are associated with long term outcomes in imatinib treated chronic myeloid leukemia patients. Eur. J. Haematol. 2014;92(4):283–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Zach O, Krieger O, Foedermayr M, Zellhofer B, Lutz D. OCT1 (SLC22A1) R61C polymorphism and response to imatinib treatment in chronic myeloid leukemia patients. Leuk. Lymphoma. 2008;49(11):2222–3.PubMedCrossRefGoogle Scholar
  67. 67.
    White DL, Saunders VA, Dang P, Engler J, Hughes TP. OCT-1 activity measurement provides a superior imatinib response predictor than screening for single-nucleotide polymorphisms of OCT-1. Leukemia. 2010;24(11):1962–5.PubMedCrossRefGoogle Scholar
  68. 68.
    Vine J, Cohen SB, Ruchlemer R, Goldschmidt N, Levin M, Libster D, Gural A, Gatt ME, Lavie D, Ben-Yehuda D, Rund D. 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. 2014;55(11):2525–31.PubMedCrossRefGoogle Scholar
  69. 69.
    Mahon FX, Belloc F, Lagarde V, Chollet C, Moreau-Gaudry F, Reiffers J, Goldman JM, Melo JV. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood. 2003;101(6):2368–73.PubMedCrossRefGoogle Scholar
  70. 70.
    Illmer T, Schaich M, Platzbecker U, Freiberg-Richter J, Oelschlägel U, von Bonin M, Pursche S, Bergemann T, Ehninger G, Schleyer E. P-glycoprotein- mediated drug efflux is a resistance mechanism of chronic myeloid leukemia cells to treatment with imatinib mesylate. Leukemia. 2004;18(3):401–8.PubMedCrossRefGoogle Scholar
  71. 71.
    Dulucq S, Bouchet S, Turcq B, Lippert E, Etienne G, Reiffers J, Molimard M, Krajinovic M, Mahon FX. Multidrug resistance gene (MDR1) polymorphisms are associated with major molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood. 2008;112(5):2024–7.PubMedCrossRefGoogle Scholar
  72. 72.
    Dulucq S, Preudhomme C, Guilhot F, Mahon FX. Is there really a relationship between Multidrug resistance gene (MDR1) polymorphisms and major molecular response to imatinib in chronic myeloid leukemia. Blood. 2010;116(26):6145–6.CrossRefGoogle Scholar
  73. 73.
    Kim DH, Sriharsha L, Xu W, Kamel-Reid S, Liu X, Siminovitch K, Messner HA, Lipton JH. Clinical relevance of a pharmacogenetic approach using multiple candidate genes to predict response and resistance to imatinib therapy in chronic myeloid leukemia. Clin. Cancer Res. 2009;15(14):4750–8.PubMedCrossRefGoogle Scholar
  74. 74.
    Takahashi N, Miura M, Scott SA, Kagaya H, Kameoka Y, Tagawa H, Saitoh H, Fujishima N, Yoshioka T, Hirokawa M, Sawada K. 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. 2010;55(11):731–7.PubMedCrossRefGoogle Scholar
  75. 75.
    Deenik W, van der Holt B, Janssen JJ, Chu IW, Valk PJ, Ossenkoppele GJ, van der Heiden IP, Sonneveld P, van Schaik RH, Cornelissen JJ. Polymorphisms in the multidrug resistance gene MDR1 (ABCB1) predict for molecular resistance in patients with newly diagnosed chronic myeloid leukemia receiving high-dose imatinib. Blood. 2010;16(26):6144–5.CrossRefGoogle Scholar
  76. 76.
    Ni LN, Li JY, Miao KR, Qiao C, Zhang SJ, Qiu HR, Qian SX. Multidrug resistance gene (MDR1) polymorphisms correlate with imatinib response in chronic myeloid leukemia. Med. Oncol. 2011;28(1):265–9.PubMedCrossRefGoogle Scholar
  77. 77.
    Maffioli M, Camós M, Gaya A, Hernández-Boluda JC, Alvarez-Larrán A, Domingo A, Granell M, Guillem V, Vallansot R, Costa D, Bellosillo B, Colomer D, Cervantes F. Correlation between genetic polymorphims 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(8):1014–9.PubMedCrossRefGoogle Scholar
  78. 78.
    Kimchi-Sarfaty C, Marple AH, Shinar S, Kimchi AM, Scavo D, Roma MI, Kim IW, Jones A, Arora M, Gribar J, Gurwitz D, Gottesman MM. Ethnicity-related polymorphisms and haplotypes in the human ABCB1 gene. Pharmacogenomics. 2007;8(1):29–39.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Picard S, Titier K, Etienne G, Teilhet E, Ducint D, Bernard MA, Lassalle R, Marit G, Reiffers J, Begaud B, Moore N, Molimard M, Mahon FX. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood. 2007;109(8):3496–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Peng B, Lloyd P, Schran H. Clinical pharmacokinetics of imatinib. Clin. Pharmacokinet. 2005;44(9):879–94.PubMedCrossRefGoogle Scholar
  81. 81.
    Iurlo A, Ubertis A, Artuso S, Bucelli C, Radice T, Zappa M, Cattaneo D, Mari D, Cortelezzi A. Comorbidities and polypharmacy impact on complete cytogenetic response in chronic myeloid leukaemia elderly patients. Eur J Intern Med. 2014;25(1):63–6.PubMedCrossRefGoogle Scholar
  82. 82.
    Ibrahim AR, Eliasson L, Apperley JF, Milojkovic D, Bua M, Szydlo R, Mahon FX, Kozlowski K, Paliompeis C, Foroni L, Khorashad JS, Bazeos A, Molimard M, Reid A, Rezvani K, Gerrard G, Goldman J, Marin D. Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy. Blood. 2011;117(14):3733–6.PubMedCrossRefGoogle Scholar
  83. 83.
    Marin D, Bazeos A, Mahon FX, Eliasson L, Milojkovic D, Bua M, Apperley JF, Szydlo R, Desai R, Kozlowski K, Paliompeis C, Latham V, Foroni L, Molimard M, Reid A, Rezvani K, de Lavallade H, Guallar C, Goldman J, Khorashad JS. 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. 2010;28(14):2381–8.PubMedCrossRefGoogle Scholar
  84. 84.
    Donato NJ, Wu JY, Stapley J, Gallick G, Lin H, Arlinghaus R, Talpaz M. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood. 2003;101(2):690–8.PubMedCrossRefGoogle Scholar
  85. 85.
    Burchert A, Wang Y, Cai D, von Bubnoff N, Paschka P, Müller-Brüsselbach S, Ottmann OG, Duyster J, Hochhaus A, Neubauer A. Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development. Leukemia. 2005;19(10):1774–82.PubMedCrossRefGoogle Scholar
  86. 86.
    Agarwal A, Eide CA, Harlow A, Corbin AS, Mauro MJ, Druker BJ, Corless CL, Heinrich MC, Deininger MW. An activating KRAS mutation in imatinib-resistant chronic myeloid leukemia. Leukemia. 2008;22(12):2269–72.PubMedCrossRefGoogle Scholar
  87. 87.
    Wang Y, Cai D, Brendel C, Barett C, Erben P, Manley PW, Hochhaus A, Neubauer A, Burchert A. Adaptive secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates imatinib and nilotinib resistance in BCR/ABL+ progenitors via JAK-2/STAT-5 pathway activation. Blood. 2007;109(5):2147–55.PubMedCrossRefGoogle Scholar
  88. 88.
    O’Hare T, Zabriskie MS, Eiring AM, Deininger MW. Pushing the limits of targeted therapy in chronic myeloid leukemia. Nat. Rev. Cancer. 2012;12(8):513–26.PubMedCrossRefGoogle Scholar
  89. 89.
    Graham SM, Jørgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L, Holyoake TL. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002;99(1):319–25.PubMedCrossRefGoogle Scholar
  90. 90.
    Mahon FX, Réa D, Guilhot J, Guilhot F, Huguet F, Nicolini F, Legros L, Charbonnier A, Guerci A, Varet B, Etienne G, Reiffers J, Rousselot P, Intergroupe Français des Leucémies Myéloïdes Chroniques. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11(11):1029–35.PubMedCrossRefGoogle Scholar
  91. 91.
    Barnes DJ, Palaiologou D, Panousopoulou E, Schultheis B, Yong AS, Wong A, Pattacini L, Goldman JM, Melo JV. Bcr-Abl expression levels determine the rate of development of resistance to imatinib mesylate in chronic myeloid leukemia. Cancer Res. 2005;65(19):8912–9.PubMedCrossRefGoogle Scholar
  92. 92.
    Kumari A, Brendel C, Hochhaus A, Neubauer A, Burchert A. Low BCR-ABL expression levels in hematopoietic precursor cells enable persistence of chronic myeloid leukemia under imatinib. Blood. 2012;119(2):530–9.PubMedCrossRefGoogle Scholar
  93. 93.
    Corbin AS, Agarwal A, Loriaux M, Cortes J, Deininger MW, Druker BJ. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Invest. 2011;121(1):396–409.PubMedCrossRefGoogle Scholar
  94. 94.
    Hamilton A, Helgason GV, Schemionek M, Zhang B, Myssina S, Allan EK, Nicolini FE, Müller-Tidow C, Bhatia R, Brunton VG, Koschmieder S, Holyoake TL. Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival. Blood. 2012;119(6):1501–10.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Ng KP, Manjeri A, Lee KL, Huang W, Tan SY, Chuah CT, Poellinger L, Ong ST. Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition. Blood. 2014;123(21):3316–26.PubMedCrossRefGoogle Scholar
  96. 96.
    Chen Y, Peng C, Abraham SA, Shan Y, Guo Z, Desouza N, Cheloni G, Li D, Holyoake TL, Li S. Arachidonate 15-lipoxygenase is required for chronic myeloid leukemia stem cell survival. J Clin Invest. 2014;124(9):3847–62.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Kobayashi CI, Takubo K, Kobayashi H, Nakamura-Ishizu A, Honda H, Kataoka K, Kumano K, Akiyama H, Sudo T, Kurokawa M, Suda T. The IL-2/CD25 axis maintains distinct subsets of chronic myeloid leukemia-initiating cells. Blood. 2014;123(16):2540–9.PubMedCrossRefGoogle Scholar
  98. 98.
    Zhang B, Li M, McDonald T, Holyoake TL, Moon RT, Campana D, Shultz L, Bhatia R. Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-cadherin and Wnt-β-catenin signaling. Blood. 2013;121(10):1824–38.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    MacLean AL, Filippi S, Stumpf MP. The ecology in the hematopoietic stem cell niche determines the clinical outcome in chronic myeloid leukemia. Proc. Natl. Acad. Sci. 2014;111(10):3883–8.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Krause DS, Lazarides K, Lewis JB, von Andrian UH, Van Etten RA. Selectins and their ligands are required for homing and engraftment of BCR-ABL1+ leukemic stem cells in the bone marrow niche. Blood. 2014;123(9):1361–71.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Zhang J, Ren X, Shi W, Wang S, Chen H, Zhang B, Wang Z, Zhou Y, Chen L, Zhang R, Lv Y, Zhou J, Nan X, He L, Yue W, Li Y, Pei X. Small molecule Me6TREN mobilizes hematopoietic stem/progenitor cells by activating MMP-9 expression and disrupting SDF-1/CXCR4 axis. Blood. 2014;123(3):428–41.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Biochemistry, Faculty of ScienceAin Shams UniversityCairoEgypt

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