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The Nucleus

, Volume 62, Issue 2, pp 155–164 | Cite as

Genetics and tyrosine kinase inhibitors of chronic myeloid leukemia

  • Bani Bandana GangulyEmail author
  • Nitin N. Kadam
Review Article
  • 35 Downloads

Abstract

Chronic myeloid leukemia (CML) is caused by a reciprocal translocation between 9q34 and 22q11, which produces a chimeric BCR-ABL oncogene located on the Philadelphia chromosome i.e. rearranged 22. The fusion gene implicates in the overexpression of tyrosine kinase through binding with ATP in signal transduction. Therefore, targeted drug development aimed at inhibitors of tyrosine kinase (TKI) and formulated imatinib, which resulted in miraculous disease free survival in majority of the CML patients. However, drug-resistance remained a problem due mainly to emergence of missense point mutations in and around the BCR-ABL kinase domain. Loss of its sensitivity to leukemic stem cells guided development of altered TKIs such as dasatinib, nilotinib, bosutinib and ponatinib—each having specific sensitivity to different amino acid residues (T315I, Y253F/H, E255K/V, M351T, G250E, F359C/V, H396R/P, M244V, E355G, F317L, M237I, Q252H/R, D276G, L248V, F486S), have been implicated in ~ 85% of CML. At chromosomal level, trisomy 8, isochromosome 17q, amplification of the Philadelphia chromosome, additional translocations and complex karyotype are described in TKI-resistant CML. Therefore, mutational events at kinase domain and additional chromosome abnormalities could be considered for development and initiation of TKI-therapy, and cross-talk of complex mutations could lead to formulation of personalized TKI.

Keywords

Chronic myeloid leukemia BCR-ABL domain mutations Complex karyotype Tyrosine kinase inhibitors 

Notes

Acknowledgement

The authors wish to acknowledge the Mahatma Gandhi Mission Trust for supporting this publication.

References

  1. 1.
    Abrahamsson AE, Geron I, Gotlib J, Dao KH, Barroga CF, et al. Glycogen synthase kinase 3 beta missplicing contributes to leukemia stem cell generation. Proc Nat Acad Sci USA. 2009;106:3925–9.CrossRefPubMedGoogle Scholar
  2. 2.
    Ai J, Tiu RV. Practical management of patients with chronic myeloid leukemia who develop tyrosine kinase inhibitor-resistant BCR-ABL1 mutations. Ther Adv Hematol. 2014;5(4):107–20.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Arora A, Scholar EM. Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther. 2005;315(3):971–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Apperley JF. Part 1: mechanisms of resistance to imatinib in chronic myeloid leukemia. Lancet Oncol. 2007;8(11):1018–29.CrossRefPubMedGoogle Scholar
  5. 5.
    Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia. Blood. 2013;122:872–84.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bewry NN, Nair RR, Emmons MF, et al. Stat3 contributes to resistance toward BCR-ABL inhibitors in a bone marrow microenvironment model of drug resistance. Mol Cancer Ther. 2008;7:169–75.CrossRefGoogle Scholar
  7. 7.
    Bitencourt R, Zalcberg I, Louro ID. Imatinib resistance: a review of alternative inhibitors in chronic myeloid leukemia. Rev Bras Hematol Hemator. 2011;33(6):470–5.  https://doi.org/10.5581/1516-8484.20110124.CrossRefGoogle Scholar
  8. 8.
    Bjorkholm M, Ohm L, Eloranta S, Derolf A, Hultcrantz M, Sjoberg J, et al. Success story of targeted therapy in chronic myeloid leukemia: a population-based study of patients diagnosed in Sweden from 1973 to 2008. J Clin Oncol. 2011;29:2514–20.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Blay JY, von Mehren M. Nilotinib: a novel selective tyrosine kinase inhibitor. Semin Oncol. 2011;38(Suppl 1):S3–9.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Boschelli F, Arndt K, Gambacorti-Passerini C. Bosutinib: a review of preclinical studies in chronic myelogenous leukaemia. Eur J Cancer. 2010;46:1781–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Brunner A, Campigotto F, Sadrzadeh H, Drapkin B, Chen Y, Neuberg D, et al. Trends in all-cause mortality among patients with chronic myeloid leukemia: a surveillance, epidemiology, and end results database analysis. Cancer. 2013;119:2620–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Burchert A, Wang Y, Cai D, et al. Compensatory PI3-kinase/Akt/mTOR activation regulates imatinib resistance development. Leukemia. 2005;19:1774–82.CrossRefPubMedGoogle Scholar
  13. 13.
    Chen YY, Peng C, Li DG, Li SG. Molecular and cellular bases of chronic myeloid leukemia. Protein Cell. 2010;1:124–32.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Chu S, Holtz M, Gupta M, et al. BCR/ABL kinase inhibition by imatinib mesylate enhances MAP kinase activity in chronic myelogenous leukemia CD34 + cells. Blood. 2004;103:3167–74.CrossRefPubMedGoogle Scholar
  15. 15.
    Cortes JE, Kantarjian HM, Brummendorf TH, Kim DW, Turkina AG, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011;118:4567–76.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Coutre PD, Giles FJ, Hochhaus A, Apperley JF, Ossenkoppele GJ, et al. Nilotinib in patients with Ph + chronic myeloid leukemia in accelerated phase following imatinib resistance or intolerance: 24-month follow-up results. Leukemia. 2012;26:1189–94.CrossRefPubMedGoogle Scholar
  17. 17.
    Druker BJ, Lydon NB. Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest. 2000;105(1):3–7.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Deininger MW, 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. Blood. 2009;114:1126.CrossRefGoogle Scholar
  20. 20.
    Deluche L, Joha S, Corm S, Daudignon A, Geffroy S, Quief S, et al. Cryptic and partial deletions of PRDM16 and RUNX1 without t(1;21)(p36;q22) and/or RUNX1-PRDM16 fusion in a case of progressive chronic myeloid leukemia: a complex chromosomal rearrangement of underestimated frequency in disease progression? Genes Chromosomes Cancer. 2008;47:1110–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Eiring AM, Deininger MW. Individualizing kinase-targeted cancer therapy: the paradigm of chronic myeloid leukemia. Genome Biol. 2014;15:461.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Eiring AM, Page BD, Kraft IL, Mason CC, Vellore NA, Resetca D, et al. Combined STAT3 and BCR-ABL1 inhibition induces synthetic lethality in therapy-resistant chronic myeloid leukemia. Leukemia. 2015;29:586–97.CrossRefPubMedGoogle Scholar
  23. 23.
    Ganesan P, Sagar TG, Dubashi B, Rajendranath R, Kannan K, Cyriac S, et al. Nonadherence to imatinib adversely affects event free survival in chronic phase chronic myeloid leukemia. Am J Hematol. 2011;86(6):471–4.CrossRefPubMedGoogle Scholar
  24. 24.
    Ganguly BB. Small-molecule inhibitors of epigenetic mutations as compelling drug-targets for myelodysplastic syndromes. Curr Cancer Drug Targets. 2017;17(7):586–602.  https://doi.org/10.2174/15680096170330145002.CrossRefPubMedGoogle Scholar
  25. 25.
    Ganguly BB, Kadam NN. Mutations of myelodysplastic syndromes (MDS): an update. Mutat Res Rev. 2016;769:47–62.  https://doi.org/10.1016/j.mrrev.2016.04.009.CrossRefGoogle Scholar
  26. 26.
    Ganguly BB, Kadam NN, Agarwal MB. Conventional and fluorescence in situ hybridization analysis of three-way complex BCR-ABL rearrangement in a chronic myeloid leukemia patient. J Cancer Res Ther. 2007;3(2):127–9.CrossRefGoogle Scholar
  27. 27.
    Golas J, Arndt K, Etienne C, Lucas J, Nardin D, Gibbons J, et al. SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Res. 2003;63:375–81.PubMedGoogle Scholar
  28. 28.
    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;293:876–80.CrossRefPubMedGoogle Scholar
  29. 29.
    Groarke JD, Cheng S, Moslehi J. Cancer-drug discovery and cardiovascular surveillance. N Engl J Med. 2013;369:1779–81.CrossRefPubMedGoogle Scholar
  30. 30.
    Guilhot F. Indications for imatinib mesylate therapy and clinical management. Oncologist. 2004;9:271–81.CrossRefPubMedGoogle Scholar
  31. 31.
    Hegedus C, Ozvegy-Laczka C, Apati A, Magocsi M, Nemet K, et al. Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: implications for altered anti-cancer effects and pharmacological properties. Br J Pharmacol. 2009;158:1153–64.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Hehlmann R, Lauseker M, Jung-Munkwitz S, Leitner A, Muller MC, Pletsch N, et al. Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-α in newly diagnosed chronic myeloid leukemia. J Clin Oncol. 2011;29:1634–42.CrossRefPubMedGoogle Scholar
  33. 33.
    Hochhaus A, Kantarjian HM, Baccarani M, Lipton JH, Apperley JF, Druker BJ, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy (erratum in Blood. 2007;110(5):1438). Blood. 2007;109(6):2303–9.Google Scholar
  34. 34.
    Ibrahim AR, Eliasson L, Apperley JF, et al. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Jabbour EJ, Kantarjian H, Eliason L, Cornelison AM, Marin D. Patient adherence to tyrosine kinase inhibitor therapy in chronic myeloid leukemia. Am J Hematol. 2012;87:687–91.CrossRefPubMedGoogle Scholar
  36. 36.
    Kantarjian HM, Shah NP, Cortes JE, Baccarani M, Agarwal MB, Undurraga MS, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2012;119:1123–9.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Khorashad JS, Eiring AM, Mason CC, et al. shRNA library screening identifies nucleocytoplasmic transport as a mediator of BCR-ABL1 kinase-independent resistance. Blood. 2015;125:1772–81.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Levinson N, Boxer S. Structural and spectroscopic analysis of the kinase inhibitor bosutinib and an isomer of bosutinib binding to the ABL tyrosine kinase domain. PLoS ONE. 2012;7:e29828.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Li S. Src-family kinases in the development and therapy of Philadelphia chromosome-positive chronic myeloid leukemia and acute lymphoblastic leukemia. Leuk Lymphoma. 2008;49(1):19–26.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Liu J, Joha S, Idziorek T, Corm S, Hetuin D, Philippe N, et al. BCR-ABL mutants spread resistance to non-mutated cells through a paracrine machanism. Leukemia. 2008;22:791–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Lombardo L, Lee F, Chen P, Norris D, Barrish J, Behnia K, et al. Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino) thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in perclinical assays. J Med Chem. 2004;47:6658–61.CrossRefPubMedGoogle Scholar
  42. 42.
    Ma L, Shan Y, Bai R, et al. A therapeutically targetable mechanism of BCR-ABL-independent imatinib resistance in chronic myeloid leukemia. Sci Tansl Med. 2014;6:252ra121.CrossRefGoogle Scholar
  43. 43.
    Marchesi V. Hematological cancer: Nilotinib reduces emergence of BCR-ABL mutations in CML. Nat Rev Clin Oncol. 2013;10:248.  https://doi.org/10.1038/nrclinonc.2013.51.CrossRefPubMedGoogle Scholar
  44. 44.
    Marin D, Bazeos A, Mahon FX, et al. 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 Off J Am Soc Clin Oncol. 2010;28(14):2381–8.CrossRefGoogle Scholar
  45. 45.
    Mitchell R, Hopcroft LEM, Baquero P, Allan EK, Hewit K, James D, et al. Targeting BCR-ABL-Independent TKI Resistance in Chronic Myeloid Leukemia by mTOR and Autophagy Inhibition. J Natl Cancer Inst. 2018;110(5):467–78.  https://doi.org/10.1093/jnci/djx236.CrossRefPubMedGoogle Scholar
  46. 46.
    Muller MC, Cortes JE, Kim DW, Druker BJ, Erben P, et al. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood. 2009;114:4944–53.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    O’Hare T, Zabriskie MS, Eiring AM, Deininger MW. Pushing the limits of targeted therapy in chronic myeloid leukemia. Nat Rev Cancer. 2012;12:513–26.CrossRefPubMedGoogle Scholar
  48. 48.
    Okabe S, Tauchi T, Tanaka Y, Ohyashiki K. Efficacy of ponatinib against ABL tyrosine kinase inhibitor-resistant leukemia cells. Biochem Biophys Res Commun. 2013;435:506–11.CrossRefPubMedGoogle Scholar
  49. 49.
    Okabe S, Tauchi T, Tanaka Y, et al. Efficacy of the dual PI3 K and mTOR inhibitor NVP-BEZ235 in combination with nilotinib against BCR-ABL-positive leukemia cells involves the ABL kinase domain mutation. Cancer Biol Ther. 2014;15:207–15.CrossRefPubMedGoogle Scholar
  50. 50.
    Ottmann O, Dombret H, Martinelli G, Simonsson B, Guilhot F, et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood. 2007;110:2309–15.CrossRefPubMedGoogle Scholar
  51. 51.
    Packer LM, Rana S, Hayward R, et al. Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia. Cancer Cell. 2011;20:715–27.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Patel AB, O’Hare T, Deininger MW. Mechanisms of resistance to ABL-kinase inhibition in CML and the development of next generation ABL kinase inhibitirs. Hematol Oncol Clin North Am. 2017;31(4):589–612.  https://doi.org/10.1016/j.hoc.2017.04.007.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Perrotti D, Jamieson C, Goldman J, Skorski T. Chronic myeloid leukemia: mechanisms of blastic transformation. J Clin Invest. 2010;120:2254–64.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Redaelli S, Piazza R, Rostagno R, Magistroni V, Perini P, Marega M, et al. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol. 2009;27:469–71.CrossRefPubMedGoogle Scholar
  55. 55.
    Remsing Rix LL, Rix U, Colinge J, Hantschel O, Bennett KL, Stranzl T, et al. Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia. 2009;23:477–85.CrossRefPubMedGoogle Scholar
  56. 56.
    Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973;243:290–3.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Sawyers CL. Opportunities and challenges in the development of kinase inhibitor therapy for cancer. Genes Dev. 2003;17(24):2998–3010.  https://doi.org/10.1101/gad.1152403.CrossRefPubMedGoogle Scholar
  58. 58.
    Schindler T, Bornmann W, Pellicena P, Miller W, Clarkoson B, Kuriyan J, et al. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science. 2000;289:1938–42.CrossRefPubMedGoogle Scholar
  59. 59.
    Scott MT, Korfi K, Saffrey P, et al. Epigenetic reprogramming sensitizes CML stem cells to combined EZH2 and tyrosine kinase inhibition. Cancer Discov. 2016;6:1248–57.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004;305(5682):399–401.  https://doi.org/10.1126/science.1099480.CrossRefPubMedGoogle Scholar
  61. 61.
    Shaker ME, Ghani A, Shiha GE, Ibrahim TM, Mehal WZ. Nilotinib induces apoptosis and autophagic cell death of activated hepatic stellate cells via inhibition of histone deacetylases. Biochim Biophys Acta. 2013;1833:1992–2003.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Shawver LK, Slamon D, Ullrich A. Smart drugs: tyrosine kinase inhibitors in cancer therapy. Cancer Cell. 2002;1(2):117–23.CrossRefPubMedGoogle Scholar
  63. 63.
    Shen C, Zhao B, Liu L, Ya-Chen Tina Shih YT. Adherence to tyrosine kinase inhibitors among Medicare Part D beneficiaries with chronic myeloid leukemia. Cancer. 2018;124(2):364–73.  https://doi.org/10.1002/cncr.3105.CrossRefPubMedGoogle Scholar
  64. 64.
    Skorski T. Genetic mechanisms of chronic myeloid leukemia blastic transformation. Curr Hematol Malig Rep. 2012;7:87–93.CrossRefPubMedGoogle Scholar
  65. 65.
    Stich W, Back F, Dorrner P, Tsirimbas A. Double Philadelphia chromosome and isochromosome 17 in the terminal phase of chronic myeloid leukemia. Klin Wochenschr. 1966;44:334–7.CrossRefPubMedGoogle Scholar
  66. 66.
    Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354:2531–41.CrossRefPubMedGoogle Scholar
  67. 67.
    Tanaka R, Kimura S, Ashihara E, Yoshimura M, Takahashi M, Wakita H, et al. Rapid automated detection of ABL kinase domain mutations in imatinib-resistant patients. Cancer Lett. 2011;312:228–34.CrossRefPubMedGoogle Scholar
  68. 68.
    Traer E, MacKenzie R, Snead J, Agarwal A, Eiring AM, O’Hare T, et al. Blockade of JAK2-mediated extrinsic survival signals restores sensitivity of CML cells to ABL inhibitors. Leukemia. 2012;26:1140–3.CrossRefPubMedGoogle Scholar
  69. 69.
    Tran H, Brunet A, Griffith EC, Greenberg ME. The many forks in FOXo’s road. Sci STKE. 2003;172:RE5.Google Scholar
  70. 70.
    Cancer Travis J. Gleevec, chapter two: new leukemia drug aims to overcome resistance. Science. 2004;305:319–21.Google Scholar
  71. 71.
    Wagle M, Eiring AM, Wongchenko M, Lu S, Guan Y, Wang Y, et al. A role of FOXO1 in BCR-ABL1-independent tyrosine kinase inhibitor resistance in chronic myeloid leukemia. Leukemia. 2016;30:1493–501.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Walker CJ, Oaks JJ, Santhanam R, et al. Preclinical and clinical efficacy of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in Ph + leukemias. Blood. 2013;122:3034–44.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Weisberg E, Manley P, Breitenstein W, Bruggen J, Cowan-Jacob S, Ray A, et al. Characterization of AMN107, a selective inhibitor of native and mutant BCR-ABL. Cancer Cell. 2005;7:129–41.CrossRefPubMedGoogle Scholar
  74. 74.
    Weisberg E, Manley PW, Cowan-Jacob SW, Hochhaus A, Griffin JD. Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukemia. Nat Rev Cancer. 2007;7:345–56.CrossRefPubMedGoogle Scholar
  75. 75.
    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.CrossRefPubMedGoogle Scholar
  76. 76.
    White DL, Saunders VA, Dang P, Engler J, Venables A, 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;110:4064–72.CrossRefPubMedGoogle Scholar
  77. 77.
    White DL, Dang P, Engler J, Frede A, Zirm 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;28:2761–7.CrossRefPubMedGoogle Scholar
  78. 78.
    Xie H, Peng C, Huang J, et al. Chronic myelogenous leukemia initiating cells require Polycomb group protein EZH2. Cancer Discov. 2016;6:1237–47.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Yang K, Fu LW. Mechanisms of resistance to BCR-ABL TKIs and the therapeutic strategies: a review. Crit Rev Oncol Hematol. 2015;93:277–92.CrossRefPubMedGoogle Scholar
  80. 80.
    Zabriskie MS, Eide CA, Tantravahi SK, Vellore NA, Estrada J, Nicolini FE, et al. 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.  https://doi.org/10.1016/j.ccr.2014.07.006.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Zhang C, Zhou SS, Li XR, Wang BM, Lin NM, et al. Enhanced antitumor activity by the combination of dasatinib and combretastain A-4 in vitro and in vivo. Oncol Rep. 2013;29:2275–82.CrossRefPubMedGoogle Scholar
  82. 82.
    Zhou T, Commodore L, Huang W, Wang Y, Thomas M, Keats J, et al. Structural mechanism of the pan-BCR-ABL inhibitor ponatinib (AP24534): lessons for overcoming kinase inhibitor resistance. Chem Biol Drug Des. 2011;77:1–11.CrossRefPubMedGoogle Scholar
  83. 83.
    Zimmermann J, Caravatti G, Mett H, Meyer T, Muller M, et al. Phenylamino-pyrimidine (PAP) derivatives: a new class of potent and selective inhibitors of protein kinase C (PKC). Arch Pharm (Weinheim). 1996;329:271–6.CrossRefGoogle Scholar
  84. 84.
    Zirm E, Spies-Weisshart B, Heidel F, Schnetzke U, Bohmer FD, et al. Ponatinib may overcome resistance of FLT3-ITD harbouring additional point mutations notably the previously refractory F6911 mutation. Br J Haematol. 2012;157:483–92.CrossRefPubMedGoogle Scholar

Copyright information

© Archana Sharma Foundation of Calcutta 2019

Authors and Affiliations

  1. 1.MGM Center for Genetic Research and DiagnosisMGM New Bombay HospitalNavi MumbaiIndia
  2. 2.MGM Institute of Health SciencesNavi MumbaiIndia

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