Mechanisms of Resistance to Targeted Therapies in Chronic Myeloid Leukemia

  • Federico Lussana
  • Tamara IntermesoliEmail author
  • Paola Stefanoni
  • Alessandro Rambaldi
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 249)


Patients with newly diagnosed chronic myeloid leukemia (CML) usually received as first-line treatment a first- or second-generation tyrosine kinase inhibitor (TKI). Although initial responses are high, therapy fails in up to 40% of patients and initial response is lost within 2 years in approximately 25% of patients. In the last few years, intensive efforts have been spent to explain treatment failure, and different mechanisms of resistance have been identified, ranging from BCR-ABL1 kinase domain mutations to lack of adherence to therapy. In this review, we briefly summarize the clinical efficacy of approved TKIs and describe the main mechanisms of TKI resistance.


Chronic myeloid leukemia Mechanisms of TKI resistance Tyrosine kinase inhibitors 


  1. Abrahamsson AE, Geron I, Gotlib J, Dao KH, Barroga CF, Newton IG, Giles FJ, Durocher J, Creusot RS, Karimi M et al (2009) Glycogen synthase kinase 3beta missplicing contributes to leukemia stem cell generation. Proc Natl Acad Sci U S A 106(10):3925–3929PubMedPubMedCentralGoogle Scholar
  2. Agarwal A, Eide CA, Harlow A, Corbin AS, Mauro MJ, Druker BJ, Corless CL, Heinrich MC, Deininger MW (2008) An activating KRAS mutation in imatinib-resistant chronic myeloid leukemia. Leukemia 22(12):2269–2272PubMedGoogle Scholar
  3. Angelini S, Soverini S, Ravegnini G, Barnett M, Turrini E, Thornquist M, Pane F, Hughes TP, White DL, Radich J 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(2):193–200PubMedPubMedCentralGoogle Scholar
  4. Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, Cervantes F, Clark RE, Cortes JE, Guilhot F et al (2013) European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 122(6):872–884PubMedPubMedCentralGoogle Scholar
  5. Bower H, Bjorkholm M, Dickman PW, Hoglund M, Lambert PC, Andersson TM (2016) Life expectancy of patients with chronic myeloid leukemia approaches the life expectancy of the general population. J Clin Oncol 34(24):2851–2857PubMedGoogle Scholar
  6. Branford S, Rudzki Z, Walsh S, Parkinson I, Grigg A, Szer J, Taylor K, Herrmann R, Seymour JF, Arthur C et al (2003) 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 102(1):276–283PubMedGoogle Scholar
  7. Branford S, Melo JV, Hughes TP (2009) Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter? Blood 114(27):5426–5435PubMedGoogle Scholar
  8. Brummendorf TH, Cortes JE, de Souza CA, Guilhot F, Duvillie L, Pavlov D, Gogat K, Countouriotis AM, Gambacorti-Passerini C (2015) Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: results from the 24-month follow-up of the BELA trial. Br J Haematol 168(1):69–81PubMedGoogle Scholar
  9. Burchert A, Wang Y, Cai D, von Bubnoff N, Paschka P, Muller-Brusselbach S, Ottmann OG, Duyster J, Hochhaus A, Neubauer A (2005) Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development. Leukemia 19(10):1774–1782PubMedGoogle Scholar
  10. Carella AM, Garuti A, Cirmena G, Catania G, Rocco I, Palermo C, Pica G, Pierri I, Miglino M, Ballestrero A et al (2010) Kinase domain mutations of BCR-ABL identified at diagnosis before imatinib-based therapy are associated with progression in patients with high Sokal risk chronic phase chronic myeloid leukemia. Leuk Lymphoma 51(2):275–278PubMedGoogle Scholar
  11. Chen Y, Hu Y, Michaels S, Segal D, Brown D, Li S (2009) Inhibitory effects of omacetaxine on leukemic stem cells and BCR-ABL-induced chronic myeloid leukemia and acute lymphoblastic leukemia in mice. Leukemia 23(8):1446–1454PubMedPubMedCentralGoogle Scholar
  12. Chomel JC, Turhan AG (2011) Chronic myeloid leukemia stem cells in the era of targeted therapies: resistance, persistence and long-term dormancy. Oncotarget 2(9):713–727PubMedPubMedCentralGoogle Scholar
  13. Choudhuri S, Klaassen CD (2006) Structure, function, expression, genomic organization, and single nucleotide polymorphisms of human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) efflux transporters. Int J Toxicol 25(4):231–259PubMedGoogle Scholar
  14. Copland M, Hamilton A, Elrick LJ, Baird JW, Allan EK, Jordanides N, Barow M, Mountford JC, Holyoake TL (2006) Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood 107(11):4532–4539PubMedGoogle Scholar
  15. Cortes JE, Kantarjian HM, Brummendorf TH, Kim DW, Turkina AG, Shen ZX, Pasquini R, Khoury HJ, Arkin S, Volkert A et al (2011) Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood 118(17):4567–4576PubMedPubMedCentralGoogle Scholar
  16. Cortes JE, Kim DW, Kantarjian HM, Brummendorf TH, Dyagil I, Griskevicius L, Malhotra H, Powell C, Gogat K, Countouriotis AM et al (2012a) Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol 30(28):3486–3492PubMedPubMedCentralGoogle Scholar
  17. Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, O’Hare T, Hu S, Narasimhan NI, Rivera VM et al (2012b) Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med 367(22):2075–2088PubMedPubMedCentralGoogle Scholar
  18. Cortes J, Lipton JH, Rea D, Digumarti R, Chuah C, Nanda N, Benichou AC, Craig AR, Michallet M, Nicolini FE et al (2012c) Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood 120(13):2573–2580PubMedPubMedCentralGoogle Scholar
  19. Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M et al (2013) A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 369(19):1783–1796PubMedGoogle Scholar
  20. Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boque C, Shah NP, Chuah C, Casanova L, Bradley-Garelik B et al (2016) Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial. J Clin Oncol 34(20):2333–2340PubMedPubMedCentralGoogle Scholar
  21. le Coutre P, Tassi E, Varella-Garcia M, Barni R, Mologni L, Cabrita G, Marchesi E, Supino R, Gambacorti-Passerini C (2000) Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. Blood 95(5):1758–1766PubMedGoogle Scholar
  22. Crossman LC, Druker BJ, Deininger MW, Pirmohamed M, Wang L, Clark RE (2005) hOCT 1 and resistance to imatinib. Blood 106(3):1133–1134. Author reply 1134PubMedGoogle Scholar
  23. 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 (2010) 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 116(26):6144–6145. Author reply 6145–6146PubMedGoogle Scholar
  24. Donato NJ, Wu JY, Stapley J, Gallick G, Lin H, Arlinghaus R, Talpaz M (2003) BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood 101(2):690–698PubMedGoogle Scholar
  25. Druker BJ, Lydon NB (2000) Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest 105(1):3–7PubMedPubMedCentralGoogle Scholar
  26. Eechoute K, Sparreboom A, Burger H, Franke RM, Schiavon G, Verweij J, Loos WJ, Wiemer EA, Mathijssen RH (2011) Drug transporters and imatinib treatment: implications for clinical practice. Clin Cancer Res 17(3):406–415PubMedGoogle Scholar
  27. Ernst T, La Rosee P, Muller MC, Hochhaus A (2011) BCR-ABL mutations in chronic myeloid leukemia. Hematol Oncol Clin North Am 25(5):997–1008. v-viPubMedGoogle Scholar
  28. Galimberti S, Cervetti G, Guerrini F, Testi R, Pacini S, Fazzi R, Simi P, Petrini M (2005) Quantitative molecular monitoring of BCR-ABL and MDR1 transcripts in patients with chronic myeloid leukemia during imatinib treatment. Cancer Genet Cytogenet 162(1):57–62PubMedGoogle Scholar
  29. Gambacorti-Passerini C, Antolini L, Mahon FX, Guilhot F, Deininger M, Fava C, Nagler A, Della Casa CM, Morra E, Abruzzese E et al (2011) Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J Natl Cancer Inst 103(7):553–561PubMedGoogle Scholar
  30. Giannoudis A, Wang L, Jorgensen AL, Xinarianos G, Davies A, Pushpakom S, Liloglou T, Zhang JE, Austin G, Holyoake TL 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(4):628–637PubMedGoogle Scholar
  31. Gioia R, Leroy C, Drullion C, Lagarde V, Etienne G, Dulucq S, Lippert E, Roche S, Mahon FX, Pasquet JM (2011) Quantitative phosphoproteomics revealed interplay between Syk and Lyn in the resistance to nilotinib in chronic myeloid leukemia cells. Blood 118(8):2211–2221PubMedGoogle Scholar
  32. Goldman JM (2012) Ponatinib for chronic myeloid leukemia. N Engl J Med 367(22):2148–2149PubMedGoogle Scholar
  33. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293(5531):876–880Google Scholar
  34. Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L, Holyoake TL (2002) Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 99(1):319–325PubMedGoogle Scholar
  35. Hantschel O, Rix U, Superti-Furga G (2008) Target spectrum of the BCR-ABL inhibitors imatinib, nilotinib and dasatinib. Leuk Lymphoma 49(4):615–619PubMedGoogle Scholar
  36. Hegedus T, Orfi L, Seprodi A, Varadi A, Sarkadi B, Keri G (2002) Interaction of tyrosine kinase inhibitors with the human multidrug transporter proteins, MDR1 and MRP1. Biochim Biophys Acta 1587(2–3):318–325PubMedGoogle Scholar
  37. Hochhaus A (2003) Cytogenetic and molecular mechanisms of resistance to imatinib. Semin Hematol 40(Supplement 2):69–79PubMedGoogle Scholar
  38. Hochhaus A, Kreil S, Corbin AS, La Rosee P, Muller MC, Lahaye T, Hanfstein B, Schoch C, Cross NC, Berger U et al (2002) Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 16(11):2190–2196PubMedGoogle Scholar
  39. Hochhaus A, O’Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L, Goldman JM, Muller MC, Radich JP, Rudoltz M et al (2009) Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 23(6):1054–1061PubMedGoogle Scholar
  40. Hochhaus A, Saglio G, Larson RA, Kim DW, Etienne G, Rosti G, De Souza C, Kurokawa M, Kalaycio ME, Hoenekopp A et al (2013) 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 121(18):3703–3708PubMedPubMedCentralGoogle Scholar
  41. Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, Baccarani M, Deininger MW, Cervantes F, Fujihara S et al (2017) Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med 376(10):917–927PubMedPubMedCentralGoogle Scholar
  42. Hoy SM (2014) Ponatinib: a review of its use in adults with chronic myeloid leukaemia or Philadelphia chromosome-positive acute lymphoblastic leukaemia. Drugs 74(7):793–806PubMedGoogle Scholar
  43. Ibrahim AR, Eliasson L, Apperley JF, Milojkovic D, Bua M, Szydlo R, Mahon FX, Kozlowski K, Paliompeis C, Foroni L et al (2011) Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy. Blood 117(14):3733–3736PubMedPubMedCentralGoogle Scholar
  44. Iqbal Z, Aleem A, Iqbal M, Naqvi MI, Gill A, Taj AS, Qayyum A, ur-Rehman N, Khalid AM, Shah IH et al (2013) Sensitive detection of pre-existing BCR-ABL kinase domain mutations in CD34+ cells of newly diagnosed chronic-phase chronic myeloid leukemia patients is associated with imatinib resistance: implications in the post-imatinib era. PLoS One 8(2):e55717PubMedPubMedCentralGoogle Scholar
  45. Iurlo A, Ubertis A, Artuso S, Bucelli C, Radice T, Zappa M, Cattaneo D, Mari D, Cortelezzi A (2014) Comorbidities and polypharmacy impact on complete cytogenetic response in chronic myeloid leukaemia elderly patients. Eur J Intern Med 25(1):63–66PubMedGoogle Scholar
  46. Jabbour E, Kantarjian H, Jones D, Talpaz M, Bekele N, O’Brien S, Zhou X, Luthra R, Garcia-Manero G, Giles F et al (2006) Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia 20(10):1767–1773PubMedGoogle Scholar
  47. Jabbour E, Kantarjian H, Jones D, Breeden M, Garcia-Manero G, O’Brien S, Ravandi F, Borthakur G, Cortes J (2008) Characteristics and outcomes of patients with chronic myeloid leukemia and T315I mutation following failure of imatinib mesylate therapy. Blood 112(1):53–55PubMedPubMedCentralGoogle Scholar
  48. Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, Moiraghi B, Shen Z, Mayer J, Pasquini R et al (2010) Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 362(24):2260–2270PubMedGoogle Scholar
  49. Kantarjian HM, Hochhaus A, Saglio G, De Souza C, Flinn IW, Stenke L, Goh YT, Rosti G, Nakamae H, Gallagher NJ et al (2011) Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol 12(9):841–851PubMedGoogle Scholar
  50. Kantarjian HM, Shah NP, Cortes JE, Baccarani M, Agarwal MB, Undurraga MS, Wang J, Ipina JJ, Kim DW, Ogura M et al (2012) Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 119(5):1123–1129PubMedPubMedCentralGoogle Scholar
  51. Khorashad JS, de Lavallade H, Apperley JF, Milojkovic D, Reid AG, Bua M, Szydlo R, Olavarria E, Kaeda J, Goldman JM et al (2008) Finding of kinase domain mutations in patients with chronic phase chronic myeloid leukemia responding to imatinib may identify those at high risk of disease progression. J Clin Oncol 26(29):4806–4813PubMedGoogle Scholar
  52. Koren-Michowitz M, Buzaglo Z, Ribakovsky E, Schwarz M, Pessach I, Shimoni A, Beider K, Amariglio N, le Coutre P, Nagler A (2014) OCT1 genetic variants are associated with long term outcomes in imatinib treated chronic myeloid leukemia patients. Eur J Haematol 92(4):283–288PubMedGoogle Scholar
  53. Lahaye T, Riehm B, Berger U, Paschka P, Muller MC, Kreil S, Merx K, Schwindel U, Schoch C, Hehlmann R et al (2005) Response and resistance in 300 patients with BCR-ABL-positive leukemias treated with imatinib in a single center: a 4.5-year follow-up. Cancer 103(8):1659–1669PubMedGoogle Scholar
  54. Larson RA, Hochhaus A, Hughes TP, Clark RE, Etienne G, Kim DW, Flinn IW, Kurokawa M, Moiraghi B, Yu R et al (2012) Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia 26(10):2197–2203PubMedGoogle Scholar
  55. Larson RA, Kim D-W, Jootar S, Pasquini R, Clark RE, Lobo C, Goldberg SL, Shibayama H, Hochhaus A, Saglio G et al (2014) ENESTnd 5-year (y) update: long-term outcomes of patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) treated with frontline nilotinib (NIL) versus imatinib (IM). J Clin Oncol 32(15_suppl):7073–7073Google Scholar
  56. Liu Y, Gray NS (2006) Rational design of inhibitors that bind to inactive kinase conformations. Nat Chem Biol 2(7):358–364PubMedGoogle Scholar
  57. Lugo TG, Pendergast AM, Muller AJ, Witte ON (1990) Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 247(4946):1079–1082PubMedGoogle Scholar
  58. Mahon FX, Belloc F, Lagarde V, Chollet C, Moreau-Gaudry F, Reiffers J, Goldman JM, Melo JV (2003) MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood 101(6):2368–2373PubMedGoogle Scholar
  59. Mahon FX, Rea D, Guilhot J, Guilhot F, Huguet F, Nicolini F, Legros L, Charbonnier A, Guerci A, Varet B et al (2010) 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 11(11):1029–1035PubMedGoogle Scholar
  60. Marin D, Ibrahim AR, Lucas C, Gerrard G, Wang L, Szydlo RM, Clark RE, Apperley JF, Milojkovic D, Bua M et al (2012) Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. J Clin Oncol 30(3):232–238PubMedGoogle Scholar
  61. Mauro MJ (2013) Overcoming resistance in chronic myelogenous leukemia. Am Soc Clin Oncol Educ Book 306–312Google Scholar
  62. Milojkovic D, Apperley J (2009) Mechanisms of resistance to imatinib and second-generation tyrosine inhibitors in chronic myeloid leukemia. Clin Cancer Res 15(24):7519–7527PubMedGoogle Scholar
  63. Neelakantan P, Gerrard G, Lucas C, Milojkovic D, May P, Wang L, Paliompeis C, Bua M, Reid A, Rezvani K et al (2013) Combining BCR-ABL1 transcript levels at 3 and 6 months in chronic myeloid leukemia: implications for early intervention strategies. Blood 121(14):2739–2742PubMedPubMedCentralGoogle Scholar
  64. Ni LN, Li JY, Miao KR, Qiao C, Zhang SJ, Qiu HR, Qian SX (2011) Multidrug resistance gene (MDR1) polymorphisms correlate with imatinib response in chronic myeloid leukemia. Med Oncol 28(1):265–269PubMedGoogle Scholar
  65. Nicolini FE, Corm S, Le QH, Sorel N, Hayette S, Bories D, Leguay T, Roy L, Giraudier S, Tulliez M et al (2006) Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(phi)-LMC GROUP). Leukemia 20(6):1061–1066PubMedGoogle Scholar
  66. Noens L, Hensen M, Kucmin-Bemelmans I, Lofgren C, Gilloteau I, Vrijens B (2014) Measurement of adherence to BCR-ABL inhibitor therapy in chronic myeloid leukemia: current situation and future challenges. Haematologica 99(3):437–447PubMedPubMedCentralGoogle Scholar
  67. O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T et al (2003) Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348(11):994–1004PubMedGoogle Scholar
  68. O’Hare T, Walters DK, Stoffregen EP, Jia T, Manley PW, Mestan J, Cowan-Jacob SW, Lee FY, Heinrich MC, Deininger MW et al (2005) In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 65(11):4500–4505PubMedGoogle Scholar
  69. O’Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, Adrian LT, Zhou T, Huang WS, Xu Q et al (2009) AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 16(5):401–412PubMedPubMedCentralGoogle Scholar
  70. O’Hare T, Zabriskie MS, Eiring AM, Deininger MW (2012) Pushing the limits of targeted therapy in chronic myeloid leukaemia. Nat Rev Cancer 12(8):513–526PubMedGoogle Scholar
  71. Peng B, Lloyd P, Schran H (2005) Clinical pharmacokinetics of imatinib. Clin Pharmacokinet 44(9):879–894PubMedGoogle Scholar
  72. Peng XX, Tiwari AK, Wu HC, Chen ZS (2012) Overexpression of P-glycoprotein induces acquired resistance to imatinib in chronic myelogenous leukemia cells. Chin J Cancer 31(2):110–118PubMedPubMedCentralGoogle Scholar
  73. Roche-Lestienne C, Soenen-Cornu V, Grardel-Duflos N, Lai JL, Philippe N, Facon T, Fenaux P, Preudhomme C (2002) Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment. Blood 100(3):1014–1018PubMedGoogle Scholar
  74. Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Yeung DT, Dang P, Goyne JM, Slader C, Filshie RJ et al (2013) Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood 122(4):515–522PubMedGoogle Scholar
  75. Rosti G, Palandri F, Castagnetti F, Breccia M, Levato L, Gugliotta G, Capucci A, Cedrone M, Fava C, Intermesoli T et al (2009) Nilotinib for the frontline treatment of Ph(+) chronic myeloid leukemia. Blood 114(24):4933–4938PubMedGoogle Scholar
  76. Rowley JD (1973) Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243(5405):290–293PubMedGoogle Scholar
  77. Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, Pasquini R, Clark RE, Hochhaus A, Hughes TP et al (2010) Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 362(24):2251–2259PubMedGoogle Scholar
  78. Shah NP (2007) Medical management of CML. Hematology Am Soc Hematol Educ Program 371–375Google Scholar
  79. Shtivelman E, Lifshitz B, Gale RP, Canaani E (1985) Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature 315(6020):550–554PubMedGoogle Scholar
  80. Shukla S, Skoumbourdis AP, Walsh MJ, Hartz AM, Fung KL, Wu CP, Gottesman MM, Bauer B, Thomas CJ, Ambudkar SV (2011) Synthesis and characterization of a BODIPY conjugate of the BCR-ABL kinase inhibitor Tasigna (nilotinib): evidence for transport of Tasigna and its fluorescent derivative by ABC drug transporters. Mol Pharm 8(4):1292–1302PubMedPubMedCentralGoogle Scholar
  81. Soverini S, Martinelli G, Rosti G, Bassi S, Amabile M, Poerio A, Giannini B, Trabacchi E, Castagnetti F, Testoni N et al (2005) ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front 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 23(18):4100–4109PubMedGoogle Scholar
  82. Soverini S, Colarossi S, Gnani A, Rosti G, Castagnetti F, Poerio A, Iacobucci I, Amabile M, Abruzzese E, Orlandi E et al (2006) Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA working party on chronic myeloid leukemia. Clin Cancer Res 12(24):7374–7379PubMedGoogle Scholar
  83. Soverini S, Gnani A, Colarossi S, Castagnetti F, Abruzzese E, Paolini S, Merante S, Orlandi E, de Matteis S, Gozzini A et al (2009) 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 114(10):2168–2171PubMedGoogle Scholar
  84. Soverini S, Hochhaus A, Nicolini FE, Gruber F, Lange T, Saglio G, Pane F, Muller MC, Ernst T, Rosti G et al (2011) BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood 118(5):1208–1215PubMedGoogle Scholar
  85. Tang C, Schafranek L, Watkins DB, Parker WT, Moore S, Prime JA, White DL, Hughes TP (2011) Tyrosine kinase inhibitor resistance in chronic myeloid leukemia cell lines: investigating resistance pathways. Leuk Lymphoma 52(11):2139–2147PubMedGoogle Scholar
  86. Vine J, Cohen SB, Ruchlemer R, Goldschmidt N, Levin M, Libster D, Gural A, Gatt ME, Lavie D, Ben-Yehuda D 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(11):2525–2531PubMedGoogle Scholar
  87. Wang Y, Cai D, Brendel C, Barett C, Erben P, Manley PW, Hochhaus A, Neubauer A, Burchert A (2007) 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 109(5):2147–2155PubMedGoogle Scholar
  88. Weisberg E, Manley PW, Breitenstein W, Bruggen J, Cowan-Jacob SW, Ray A, Huntly B, Fabbro D, Fendrich G, Hall-Meyers E et al (2005) Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 7(2):129–141PubMedGoogle Scholar
  89. White DL, Saunders VA, Dang P, Engler J, Venables A, Zrim S, Zannettino A, Lynch K, Manley PW, Hughes T (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(12):4064–4072PubMedGoogle Scholar
  90. White DL, Dang P, Engler J, Frede A, Zrim S, Osborn M, Saunders VA, Manley PW, Hughes TP (2010a) 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 28(16):2761–2767PubMedGoogle Scholar
  91. White DL, Saunders VA, Dang P, Engler J, Hughes TP (2010b) OCT-1 activity measurement provides a superior imatinib response predictor than screening for single-nucleotide polymorphisms of OCT-1. Leukemia 24(11):1962–1965PubMedGoogle Scholar
  92. Widmer N, Colombo S, Buclin T, Decosterd LA (2003) Functional consequence of MDR1 expression on imatinib intracellular concentrations. Blood 102(3):1142PubMedGoogle Scholar
  93. Willis SG, Lange T, Demehri S, Otto S, Crossman L, Niederwieser D, Stoffregen EP, McWeeney S, Kovacs I, Park B et al (2005) High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy. Blood 106(6):2128–2137PubMedGoogle Scholar
  94. Zhang H, Li S (2013) Molecular mechanisms for survival regulation of chronic myeloid leukemia stem cells. Protein Cell 4(3):186–196PubMedPubMedCentralGoogle Scholar

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Authors and Affiliations

  • Federico Lussana
    • 1
  • Tamara Intermesoli
    • 1
    Email author
  • Paola Stefanoni
    • 1
  • Alessandro Rambaldi
    • 1
    • 2
  1. 1.Hematology and Bone Marrow Transplant UnitASST Papa Giovanni XXIII BergamoBergamoItaly
  2. 2.Department of Oncology and HematologyUniversità degli Studi di MilanoMilanItaly

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