Browse > Article
http://dx.doi.org/10.14456/apjcp.2016.49/APJCP.2016.17.7.3025

Tyrosine Kinase Inhibitors in Ph+ Chronic Myeloid Leukemia Therapy: a Review  

Shah, Krupa (Medicinal Chemistry & Pharmacogenomics, The Gujarat Cancer & Research Institute)
Parikh, Sonia (Dept. of Medical oncology, The Gujarat Cancer & Research Institute)
Rawal, Rakesh (Medicinal Chemistry & Pharmacogenomics, The Gujarat Cancer & Research Institute)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.17, no.7, 2016 , pp. 3025-3033 More about this Journal
Abstract
Chronic myeloid leukaemia (CML) is a clonal myeloproliferative hematopoietic stem cell disorder. Deregulated BCR-ABL fusion tyrosine kinase activity is the main cause of CML disease pathogenesis, making BCR-ABL an ideal target for inhibition. Current tyrosine kinase inhibitors (TKIs) designed to inhibit BCR-ABL oncoprotein activity, have completely transformed the prognosis of CML. Interruption of TKI treatment leads to minimal residual disease reside (MRD), thought to reside in TKI-insensitive leukaemia stem cells which remain a potential reservoir for disease relapse. This highlights the need to develop new therapeutic strategies for CML either as small molecule master TKIs or phytopharmaceuticals derived from nature to achieve chronic molecular remission. This review outlines the past, present and future therapeutic approaches for CML including coverage of relevant mechanisms, whether ABL dependent or independent, and epigenetic factors responsible for developing resistance against TKIs. Appearance of mutant clones along the course of therapy either pre-existing or induced due to therapy is still a challenge for the clinician. A proposed in-vitro model of generating colony forming units from CML stem cells derived from diagnostic samples seems to be achievable in the era of high throughput technology which can take care of single cell genomic profiling.
Keywords
Tyrosine kinase inhibitors; targeted therapy; minimal residual disease; colony forming units;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Mello JV, Chuah C (2007). Resistance to imatinib mesylate in chronic myeloid
2 Meng Y, Li Y, Li J, et al (2007). (-)Gossypol and its combination with imatinib induce apoptosis in human chronic myeloid leukemic cells. Leuk lymphoma, 48, 2204-12.   DOI
3 Nimmanapalli R, Fuino L, Stobaugh C, et al (2003). Co treatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl-positive human acute leukemia cells. Blood, 101, 3236-9.   DOI
4 Nimmanapalli R, O'Bryan E, Bhalla K (2001). Geldanamycin and its analogue 17-allylamino-17-demethoxygeldanamycin lowers Bcr-Abl levels and induces apoptosis and differentiation of Bcr- Abl-positive human leukemic blasts. Cancer Res, 61, 1799-804.
5 Nowell PC & Hungerford DA (1960). A minute chromosome in human chronic granulocytic leukemia. Science, 142, 1497.
6 Nowell PC and Hungerford DA. (1960).Chromosome studies on normal and leukemic human leukocytes. J National Cancer Institute, 25, 85-109,
7 O'Brien SG, F. Guilhot, RA. Larsonet, et al (2003). Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. New England J Med, 348, 994-1004.   DOI
8 O'Brien SG, Guilhot F, Larson RA, et al (2003). Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med, 348, 994-1004   DOI
9 Ahmed N, Laverick L, Sammons J, et al (2001). Ajoene, a garlicderived natural compound, enhances chemotherapy-induced apoptosis in human myeloid leukaemia CD34-positive resistant cells. Anticancer Res, 21, 3519-23.
10 Cortes J, Kim DW, Raffoux E et al (2008). Efficacy and safety of dasatinib in imatinib-resistant or - intolerant patients with chronic myeloid leukemia in blast phase. Leukemia. 22, 2176-83.   DOI
11 Cortes JE, Kantarjian HM, Brummendorf TH, et al (2011). Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive CML patients with resistance or intolerance to imatinib. Blood, 118, 4567-8   DOI
12 Cortes JE, Kim DW, Pinilla-Ibarz J, et al (2012). PACE: A pivotal phase II trial of ponatinib in patients with CML and Ph+ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation. J Clin Oncol, 30, 6503.
13 Cortes JE, Kim DW, Pinilla-Ibarz J, et al (2013). A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med, 369, 1783-96.   DOI
14 Cortes JE, Kim DW, Kantarjian HM (2012) Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol, 1, 3486-92.
15 Deininger M, Buchdunger E, Druker BJ (2005). The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood, 105, 2640-53.   DOI
16 Hershkovitz O, Granot G, Ovcharenko A, et al. (2012) Downregulation of mir-31, mir-155, and mir-564 in chronic myeloid leukemia cells. PLoS ONE, 7, 35501.   DOI
17 Gorre ME, Mohammed M, Ellwood K, et al (2001). Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science, 293, 876-80.   DOI
18 Hehlmann R, Hochhaus A, Baccarani M, et al (2007). European leukemia net. chronic myeloid leukaemia. Lancet, 370, 342-50.   DOI
19 Heinrich C, Griffith J., Druker J.et al (2000). Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood, 96, 925-32.
20 Hochhaus A, Baccarani M, Deininger M et al (2008). Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia, 22, 1200-6.   DOI
21 Hochhaus A, Kreil S, Corbin AS et al (2002). Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia, 16, 2190-6.   DOI
22 Hu Y, Swerdlow S, DuffyTMet al (2006). Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph_ leukemia in mice. Proc Natl Acad Sci U S A, 103, 16870-5.   DOI
23 Hughes TP, Hochhaus A, Branford S, et al (2010). Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood, 116, 3758-65.   DOI
24 Illmer T, Schaich M, Platzbecker U et al (2004). P-glycoproteinmediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate. Leukemia, 18, 401-8.   DOI
25 Bonifacio M, Rigo A, Guardalben E, et al (2012). a-bisabolol is an effective proapoptotic agent against BCR-ABL+ Cells in synergism with imatinib and nilotinib. Plos One, 7, 46674.   DOI
26 Markus D, Maciej S (2008). Cytotoxic effects of a combination of three natural
27 Angelo C, Susan B, Michael D, et al (2013). What challenges remain in chronic myeloid leukemia research? Haematologica, 98, 1168-72.   DOI
28 Apperley JF, Cortes JE, Kim DW et al (2009). Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START a trial. J Clin Oncol, 27, 3472-9.   DOI
29 Biggs JC, Szer J, Crilley P, et al (1992). Treatment of chronic myeloid leukemia with allogeneic bone marrow transplantation after preparation with BuCy2. Blood, 80, 1352-7.
30 Bing C, Duncan M, Jorge C, et al (2010). The elusive CML stem cell: does it matter and how do we eliminate it? Semin Hematol, 47, 362-370.   DOI
31 Branford S, Rudzki Z, Walsh S et al (2003). Detection of BCRABL 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, 276 -283.   DOI
32 Buchdunger E, Cioffi CL, Law N (2000). Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther, 295, 139-45.
33 Calabretta B. and Perrotti D. (2004).The biology of CML blast crisis. Blood, 103, 4010-22.   DOI
34 Chen Y, Peng C, Li D, et al (2010). Molecular and cellular bases of chronic myeloid leukemia. Protein Cell, 1, 124-32.   DOI
35 Chan WW, Wise SC, Kaufman MD, et al (2011). Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036. Cancer Cell, 19, 556-68.   DOI
36 Chandramohan R, Bharat D, Aparna A (2012). Anti-leukemic effects of gallic acid on human leukemia K562 cells: downregulation of COX-2, inhibition of BCR/ABL kinase and $NF-{\kappa}B$ inactivation. Toxicol In Vitro, 26, 396-405.   DOI
37 Cheetham GM, Charlton PA, Golec JM, et al (2007). Structural basis for potent inhibition of the Aurora kinases and a T315I multi-drug resistant mutant form of Abl kinase by VX-680. Cancer Lett, 251, 323-9.   DOI
38 Cohen MH, Williams G, Johnson JR, et al (2002). Approval summary for matinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res, 8, 935-42
39 Colavita I, Esposito N, Martinelli R, et al (2010). Gaining insights into the Bcr-Abl activity-independent mechanisms of resistance to imatinib mesylate in KCL22 cells: a comparative proteomic approach. Biochim Biophys Acta, 1804, 1974-87.   DOI
40 Deininger MW, Goldman JM, Melo JV (2000). The molecular biology of chronic myeloid leukemia. Blood, 96, 3343-56.
41 Deininger W, Goldman M, Lydon N. et al (1997). The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood, 90, 3691-8.
42 Desai UN, Shah KP, Mirza SH (2015). Enhancement of the cytotoxic effects of cytarabine in synergism with hesperidine and silibinin in acute myeloid leukemia: An in-vitro approach. J Cancer Res Ther, 11, 352-7.   DOI
43 Soverini S, Martinelli G, Rosti G 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, 4100-9.   DOI
44 Shah NP, Kim DW, Kantarjian H, et al (2010). Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib. Haematologica, 95,232-240.   DOI
45 Shah NP, Tran C, Lee FY, et al (2004). Overriding imatinib resistance with a novel ABL kinase inhibitor. Science, 305, 399-401.   DOI
46 Soverini S, Colarossi S, Gnani A, 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, 7374 -9.   DOI
47 Sun B, Jiang G, Zaydan MA et al (2001). ABL1 promoter methylation can exist independently of BCR-ABL transcription in chronic myeloid leukemia hematopoietic progenitors. Cancer Res, 15, 6931-7.
48 Talpaz M, Shah NP, Kantarjian H et al (2006). Dasatinib in imatinib-resistant Philadelphia chromosome positive leukemias. N Engl J Med, 354, 2531-41.   DOI
49 Talpaz M, Silver T, Druker J et al (2002). Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood, 99, 1928-37.   DOI
50 Can G, Cakir Z, Kartal M, et al (2012). Apoptotic effects of resveratrol, a grape polyphenol, on imatinib-sensitive and resistant K562 chronic myeloid leukemia cells. Anticancer Res, 32, 2673-8.
51 Giles FJ, Larson RA, Kantarjian HM, et al (2008). Nilotinib in patients (pts) with philadelphia chromosome-positive (ph+) chronic myelogenous leukemia in Blast Crisis (CML-BC) who are resistant or intolerant to imatinib. J Clin Oncol, 26, 701.
52 compounds to leukemia cells in vitro. Cancer Therapy, 6, 733-740.
53 Copland M, Hamilton A, Eirick LJ, et al (2006). Dasatinib (BMS-354825) targets an earlier progenitor population than Imatinib in primary CML but does not eliminate the quiescent fraction. Blood, 107, 4532-39.   DOI
54 Cortes J (2004). Natural history and staging of chronic myelogenous leukemia. Hematol Oncol Clin North Am, 18, 569-84.   DOI
55 Gambacorti C, Cortes J, Kim D, et al (2014). Safety of bosutinib versus imatinib in the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia. Am J Hematol, 89, 947-53.   DOI
56 Gambacorti CB, Rossi F, Verga M, et al (2002). Differences between in vivo and in vitro sensitivity to Imatinib of Bcr/Abl+ cells obtained from leukemic patients. Blood Cells Mol Dis, 28, 361-72.   DOI
57 Tokarski JS, Newitt JA, Chang CY, et al (2006). The structure of Dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinibresistant ABL mutants. Cancer Res. 66, 5790-7.   DOI
58 Gambacorti-Passerini C, Barni R, le Coutre P et al (2000). Role of alpha1 acid glycoprotein in the in vivo resistance of human BCR-ABL leukemic cells to the abl inhibitor STI571. J Natl Cancer Inst, 92, 1641-50.   DOI
59 Gambacorti-PC, Brummendorf T, Kantarjian H, et al (2007). Bosutinib (SKI-606) exhibits clinical activity in patients with Philadelphia chromosome positive CML or ALL who failed imatinib. J Clin Oncol, 25, 7006.
60 Geylani C, Zeynep C, Melis K (2012). Apoptotic effects of resveratrol, a grape polyphenol, on imatinib-sensitive and resistant K562 chronic myeloid leukemia cells. Anticancer Res, 32, 72673-2678.
61 Gishizky ML, Johnson-White J, Witte ON (1993). Efficient transplantation of BCR-ABL-induced chronic myelogenous leukemia-like syndrome in mice. Proc Natl Acad Sci U S A, 90, 3755-3759.   DOI
62 Goldman JM (2010). Chronic myeloid leukemia: a historical perspective. Seminars Hematol, 47, 302-11.   DOI
63 Gorre ME, Ellwood K, Chiosis G (2002). BCR-ABL point mutants isolated from patients with imatinib mesylateresistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90. Blood, 100, 3041-4.   DOI
64 Faderl S, Talpaz M, Estrov Z et al (1999). Chronic myelogenous leukemia: biology and therapy. Ann Intern Med, 131, 207-19.   DOI
65 Donato NJ, Wu JY, Stapley J et al (2003). BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood, 101, 690-8.   DOI
66 Druker J, Tamura S, Buchdunger E, et al (1996). Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med, 2, 561-6.   DOI
67 Edurne San Jose-Eneriz et al (2009). MicroRNA expression profiling in Imatinib-resistant Chronic Myeloid Leukemia patients without clinically significant ABL1-mutations. Molecular Cancer, 8, 69   DOI
68 Fiskus W, Pranpat M, Bali P, et al (2006). Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against Bcr-Abl expressing human leukemia cells. Blood, 108, 645-52.   DOI
69 Jelinek J, Gharibyan V, Estecio, et al. (2011) Aberrant DNA Methylation Is Associated with Disease Progression, Resistance to Imatinib and Shortened Survival in Chronic Myelogenous Leukemia. PLoS ONE, 6, 22110.   DOI
70 Jamshid K, Todd K, Philippe S, et al (2013). BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML: frequency and clonal relationships. Blood, 121, 489-98.   DOI
71 Jiang X, Delaney A, Eaves A, et al (2005) Leukemic stem cells from CML patients have uniquely elevated BCR-ABL activity explaining their selective resistance to Imatinib mesylate but also contain subpopulations with kinase mutations. Exp Hematol, 33, 50.
72 Jorgensen HG, Elliott MA, Allan EK, et al (2002). Alpha1-acid glycoprotein expressed in the plasma of chronic myeloid leukemia patients does not mediate significant in vitro resistance to STI571. Blood, 99, 713-15.   DOI
73 Kantarjian H, Cortes J, Kim DW, et al (2009). Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median followup. Blood, 113, 6322-9.   DOI
74 Kantarjian H, Giles F, Wunderle L, et al (2006). Nilotinib in imatinib-resistant CML and Philadelphia chromosomepositive ALL. N Engl J Med, 354, 2542-1.   DOI
75 Kantarjian H, Shah NP, Hochhaus A, et al (2010). Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med, 362, 2260-70.   DOI
76 Kantarjian H, Sawyers C, Hochhaus A, et al (2002). Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med, 346, 645-52.   DOI
77 Galimberti S., Cervetti G., Guerrini F, et al (2005). Quantitative molecular monitoring of BCR-ABL and MDR1 transcripts in patients with chronic myeloid leukaemia during Imatinib treatment. Cancer Genet Cytogenet, 162, 57-62   DOI
78 Flamant S, Ritchie W, Guilhot J, et al (2010). Micro-RNA response to imatinib mesylate in patients with chronic myeloid leukemia. Haematologica, 95, 1325-33.   DOI
79 Flamant S, Ritchie W, Guilhot J, et al (2010). Micro-RNA response to Imatinib mesylate in patients with chronic myeloid leukemia. Haematologica, 95, 1325-33.   DOI
80 Fontana S, Alessandro R, Barranca M, et al. (2007) Comparative proteome profiling and functional analysis of chronic myelogenous leukemia cell lines. J Proteosome Res, 6, 4330-42.   DOI
81 Galton DA (1953). Myleran in chronic myeloid leukaemia; results of treatment. Lancet, 264, 208-13.
82 Katerina P, Jitka K, Tomas Stopka (2013). Role of Epigenetics in Chronic Myeloid Leukemia. Curr Hematol Malig Rep 8, 28-36.   DOI
83 Kantarjian HM, Giles FJ, Bhalla KN, et al (2011). Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood, 117, 1141-5.   DOI
84 Kantarjian HM, O'Brien S, Cortes JE, et al (2003). Complete cytogenetic and molecular responses to interferon-alphabased therapy for chronic myelogenous leukemia are associated with excellent long-term prognosis. Cancer, 97, 1033-41.   DOI
85 Kantarjian HM, Talpaz M, Giles F et al (2006). New insights into the pathophysiology of chronic myeloid leukemia and imatinib resistance. Ann Intern Med, 145, 913-23.   DOI
86 Kastner R, Zopf A, Preuner S et.al (2014). Rapid identification of compound mutations in patients with Philadelphia-positive leukaemias by long-range next generation sequencing. EurJ Cancer, 50, 793-800.   DOI
87 Katerina P (2011). Expression patterns of microRNAs associated with CML phases and their disease related targets. Mol Cancer, 10, 41.   DOI
88 La Rosee P, Shen L, Stoff EP, et al (2003). No correlation between the proliferative status of Bcr-Abl positive cell lines and the proapoptotic activity of Imatinib mesylate (Gleevec/Glivec). Hematol J, 4, 413-19.   DOI
89 le Coutre P, Kreuzer KA, Na IK et al (2002). Determination of alpha-1 acid glycoprotein in patients with Ph_ chronic myeloid leukemia during the first 13 weeks of therapy with STI571. Blood Cells Mol Dis, 28, 75-85.   DOI
90 Visani G, Russo D, Ottaviani E, et al (1997). Effects of homoharringtonine alone and in combination with alpha interferon and cytosine arabinoside on 'in vitro' growth and induction of apoptosis in chronic myeloid leukemia and normal hematopoietic progenitors. Leukemia, 11, 624-8.   DOI
91 Weisberg E, Manley PW, Breitenstein W, et al (2005). Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell, 7, 129-141.   DOI
92 White DL, Saunders VA, Dang P et al (2010) OCT-1 activity measurement provides a superior imatinib response predictor than screening for single-nucleotide polymorphisms of OCT-1. Leukemia, 24, 1962-5.   DOI
93 White DL, Saunders VA, Dang P, et al (2006). 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, 108, 697-704.   DOI
94 White DL, Saunders VA, Dang P, et al (2008). CML patients with low OCT-1 activity achieves better molecular responses on high dose Imatinib than on standard dose. Blood, 112, 3187.
95 Pan L, Chai HB, Kinghorn A (2012).Discovery of new anticancer agents from higher plants. Front Biosci, 1, 142-156.
96 O'Hare T, Shakespeare WC, Zhu X, et al (2009). AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and and overcomes mutation-based resistance. Cancer Cell, 16, 401-12.   DOI
97 O'Hare T, Walters DK, Stoffregen EP, 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, 4500-5.   DOI
98 Okuda K, Weisberg E, Gilliland D. G, et al (2001). ARG tyrosine kinase activity is inhibited by STI571. Blood, 97, 2440-8.   DOI
99 Puissant A, Grosso S, Jacquel A, (2008). Imatinib mesylateresistant human chronic myelogenous leukemia cell lines exhibit high sensitivity to the phytoalexin resveratrol. FASEB J, 22, 1894-904.   DOI
100 Pizzatti L, Sa LA, de Souza JM, et al (2006). Altered protein profile in chronic myeloid leukemia chronic phase identified by a comparative proteomic study. Biochim Biophys Acta. 1764, 929-42.   DOI
101 Puttini M, Coluccia AM, Boschelli F, et al (2006). In vitro and in vivo activity of SKI-606, a novel Src-Abl inhibitor, against imatinib-resistant Bcr-Abl+ neoplastic cells. Cancer Res, 66, 11314-22.   DOI
102 Rowley JD (1973). A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature, 243, 290-3.   DOI
103 Quintas CA, Cortes J (2009). Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood, 113, 1619-30.   DOI
104 Redaelli S, Piazza R, Rostagno R, et al (2009). Activity of bosutinib, dasatinib, and nilotinib against 18 imatinibresistant BCR/ABL mutants. J Clin Oncol, 27, 469-71.   DOI
105 Rohrabacher M. and Hasford J. (2009). Epidemiology of chronic myeloid leukaemia (CML). Best Practice Res, 22, 295-302.
106 Saglio G, Hochhaus A, Goh YT, et al (2010). Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer, 116, 3852-61.   DOI
107 Saglio G, Kim DW, Issaragrisil S, et al (2010). Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med, 362, 2251-9.   DOI
108 Yu C, Rahmani M, Almenara J, et al (2003). Histone deacetylase inhibitors promote STI571-mediated apoptosis in STI571-sensitive and -resistant Bcr/Abl+ human myeloid leukemia cells. Cancer Res, 63, 2118-26.
109 Wu LX, Wu Y, Chen RJ, et al (2014). Curcumin derivative C817 inhibits proliferation of imatinib-resistant chronic myeloid leukemia cells with wild-type or mutant Bcr-Abl in vitro. Acta Pharmacol Sin, 35, 401-9.   DOI
110 Yang M, Yan Li, Jing Li, et al (2007). (-)Gossypol and its combination with imatinib induce apoptosis in human chronic myeloid leukemic cells. Leukemia Lymphoma, 48, 2204-12.   DOI
111 Yu C, Rahmani M, Conrad D, et al (2003). The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571. Blood, 102, 3765-74.   DOI
112 Zhang H, Trachootham D, Lu W, et al (2008). Effective killing of Gleevec-resistant CML cells with T315I mutation by a natural compound PEITC through redox-mediated mechanism. Leukemia, 22, 1191-9.   DOI
113 Zhang J, Adrian J, Jahnke W, et al (2010). Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature, 463, 501-6.   DOI
114 Zhu XS, Lin ZY, DU J, et al (2014). Clinical significance of BCR-ABL fusion gene subtypes in chronic myelogenous and acute lymphoblsticleukemias. Asian Pac J Cancer Prev, 15, 4773-80.   DOI
115 Lubbert M (2000). DNA methylation inhibitors in the treatment of leukemias, myelodysplastic syndromes and hemoglobinopathies: clinical results and possible mechanisms of action. Curr Top Microbiol Immunol, 249, 135-64.
116 SanJose E, Roman J, Jimenez A et al (2009). MicroRNA expression profiling in Imatinib-resistant chronic myeloid leukemia patients without clinically significant ABL1-mutations. Molecular Cancer, 8, 69.   DOI
117 Sawyers CL (1999). Chronic myeloid leukemia. N Engl J Med, 340, 1330-40.   DOI
118 Shah NP, Kantarjian HM, Kim DW, et al (2008). Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic phase chronic myeloid leukemia. J Clin Oncol, 26, 3204-12.   DOI
119 le Coutre P, Tassi E, Varella-Garcia M, et al (2000). Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. Blood, 95, 1758-66.
120 Lombardo LJ, Lee FY, Chen P, et al (2004). Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4ylamino) thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem, 47, 6658-61.   DOI
121 Lucas DM, Still PC, Perez LB, et al (2010) Potential of Plant-Derived Natural Products in the Treatment of Leukemia and Lymphoma. Curr Drug Targets, 11, 812-22.   DOI
122 Mahon FX, Deininger MW, Schultheis B, et al (2000). Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood, 96, 1070-9.
123 Marina B, Harvey L (2011). MicroRNAs: the primary cause or a determinant of progression in leukemia? Expert Rev Hematol, 4, 121-3.   DOI