Novel combination treatments targeting chronic myeloid leukemia stem cells

Clinical Lymphoma, Myeloma and Leukemia

Volumn 12, Issue 2, 2012, Pages 94-105

  Al Baghdadi, Tareq ^a   Abonour, Rafat ^a   Boswell, H Scott ^a,b  

^a INDIANA UNIVERSITY   (United States)

^b RICHARD L ROUDEBUSH VETERANS AFFAIRS MEDICAL CENTER   (United States)

Author keywords

BCR ABL inhibitors; Chronic myeloid leukemia; Dasatinib; Imatinib; Nilotinib; Progenitor cells; Stem cells; Tyrosine kinase inhibitors

Indexed keywords

ARACHIDONATE 5 LIPOXYGENASE; BOSUTINIB; CYCLOOXYGENASE 2; DASATINIB; HEAT SHOCK PROTEIN 90; HISTONE DEACETYLASE; HOMOHARRINGTONINE; IMATINIB; JANUS KINASE 2; NILOTINIB; PROMYELOCYTIC LEUKEMIA PROTEIN; PROTEIN BCL 2; RETASPIMYCIN; TRANSFORMING GROWTH FACTOR BETA; VORINOSTAT; ZILEUTON;

CD34 SELECTION; CHRONIC MYELOID LEUKEMIA; HEDGEHOG; HUMAN; IN VITRO STUDY; NONHUMAN; OXIDATIVE STRESS; REVIEW; STEM CELL; STEM CELL TRANSPLANTATION;

ANTINEOPLASTIC AGENTS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; FUSION PROTEINS, BCR-ABL; HUMANS; LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE; MOLECULAR TARGETED THERAPY; NEOPLASTIC STEM CELLS; PROTEIN KINASE INHIBITORS; SIGNAL TRANSDUCTION;

EID: 84858987848     PISSN: 21522650     EISSN: 21522669     Source Type: Journal    
DOI: 10.1016/j.clml.2011.10.003     Document Type: Review

References (172)

1. American Cancer Society. Leukemia-Chronic Myeloid (Myelogenous). Available at: http://www.cancer.org/Cancer/Leukemia-ChronicMyeloidCML/ DetailedGuide/index. Accessed October 17, 2011.
2. Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 2009; 27:6041-51.
3. de Lavallade H, Apperley JF, Khorashad JS, et al. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol 2008; 26:3358-63.
4. Michallet M, Morra E, Steegman J, et al. Imatinib resistance and/or intolerance in clinical practice in Europe. The "Unmet Needs in CML and Ph+ ALL" (UNIC) study. Blood 2007; 110:1951.
5. Lucas CM, Wang L, Austin GM, et al. A population study of imatinib in chronic myeloid leukaemia demonstrates lower efficacy than in clinical trials. Leukemia 2008; 22:1963-6.
6. Davis C, Sanders L, Hirji I, et al. Resistance to imatinib among patients in chronic phase (CP) of chronic myelogenous leukemia (CML) in clinical practice. J Clin Oncol 2008; 26:abstract 6595. Available at: www.asco.org. Accessed November 18, 2011.
7. Kantarjian H, Cortes J, Kim D-W, et al. 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 follow-up. Blood 2009; 113:6322-9.
8. Kantarjian HM, Giles FJ, Bhalla KN, et al. Nilotinib is effective in patients with chronic myeloid leukemia in CP after imatinib resistance or intolerance: 24-month follow-up results. Blood 2011; 117:1141-5.
9. Le Coutre PD, Giles F, Hochhaus A, et al. Nilotinib in chronic myeloid leukemia patients in accelerated phase (CML-AP) with imatinib (IM) resistance or intolerance: longer follow-up results of a phase II study. J Clin Oncol 2009; 27(suppl):abstract 7057. Available at: www.asco.org. Accessed November 18, 2011.
10. Giles FJ, Kantarjian H, Le Coutre PD, et al. Use of nilotinib to induce responses with 24-month (mo) minimum follow-up in patients (pts) with chronic myeloid leukemia in blast crisis (CML-BC) resistant to or intolerant of imatinib. J Clin Oncol 2010; 28(suppl):abstract 6510. Available at: www.asco.org. Accessed November 18, 2011.
11. Saglio G, Hochhaus A, Goh YT, et al. Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study. Cancer 2010; 116:3852-61.
12. Shah NP, Kim D-W, Kantarjian H, et al. Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in CP chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib. Haematologica 2010; 95:232-95.
13. Graham SM, Jørgensen HG, Allan E, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 2002; 99:319-25.
14. Holtz MS, Slovak ML, Zhang F, et al. Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation. Blood 2002; 99:3792-800. (Pubitemid 34534553)
15. + cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment. Blood 2005; 105:2093-8.
16. Copland M, Hamilton A, Elrick LJ, et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood 2006; 107:4532-9. (Pubitemid 43801382)
17. Jørgensen HG, Allan EK, Jordanides NE, et al. Nilotinib exerts equipotent anti-proliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells. Blood 2007; 109:4016-9. (Pubitemid 46641755)
18. Lemoli RM, Salvestrini V, Bianchi E, et al. Molecular and functional analysis of the stem cell compartment of chronic myelogenous leukemia reveals the presence of a CD34- cell population with intrinsic resistance to imatinib. Blood 2009; 114:5191-200.
19. Perrotti D, Jamieson C, Goldman J, et al. Chronic myeloid leukemia: mechanisms of blastic transformation. J Clin Invest 2010; 120:2254-64.
20. Rice KN, Jamieson CHM. Molecular pathways to CML stem cells. Int J Hematol 2010; 91:748-52.
21. Faderl S, Talpaz M, Estrov Z, et al. The biology of chronic myeloid leukemia. N Engl J Med 1999; 341:164-72. (Pubitemid 29325745)
22. Bartram CR, de Klein A, Hagemeijer A, et al. Translocation of c-abl oncogene correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukaemia. Nature 1983; 306:277-306.
23. Groffen J, Stephenson JR, Heisterkamp N, et al. Philadelphia chromosome breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 1984; 36:93-9. (Pubitemid 14155374)
24. Lugo TG, Pendergast AM, Muller AJ, et al. Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 1990; 247:1079-82.
25. O'Hare T, Deininger MWN, Eide CA, et al. Targeting the BCR-ABL signaling pathway in therapy-resistant Philadelphia chromosome-positive leukemia. Clin Cancer Res 2011; 17:212-21.
26. Quintás-Cardama A, Cortes J. Molecular biology of bcr-abl1 positive chronic myeloid leukemia. Blood 2009; 113:1619-30.
27. Druker BJ, Tamura S, Buchdunger E, et al. Effects of selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996; 2:561-6.
28. Pardanani A, Tefferi A. Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders. Blood 2004; 104:1931-9. (Pubitemid 39297841)
29. O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed CP myeloid leukemia. N Engl J Med 2003; 348:994-1004. (Pubitemid 36302244)
30. White DL, Dang P, Engler J, 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.
31. Hochhaus A, La Rosée P, Müller MC, et al. Impact of BCR-ABL mutations on patients with chronic myeloid leukemia. Cell Cycle 2011; 10:250-60.
32. Hughes TP, Kaeda J, Branford S, et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 2003; 349:1423-32. (Pubitemid 37211057)
33. Hughes TP, Hochhaus A, Branford S, et al. 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 2010; 116:3758-65.
34. Müller MC, Hochhaus A, Lauseker M, et al. Molecular response <1% BCR-ABL IS at 12 months is associated with improved overall and progression-free survival. The randomized German CML-Study IV. Blood 2010; 116:abstract 669.
35. Lombardo LJ, Lee FY, Chen P, 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 preclinical assays. J Med Chem 2004; 47:6658-61. (Pubitemid 40053752)
36. Chen Z, Lee FY, Bhalla KN, et al. Potent inhibition of platelet-derived growth factor-induced responses in vascular smooth muscle cells by BMS-354825 (dasatinib). Mol Pharmacol 2006; 69:1527-33.
37. Schittenhelm M, Shiraga S, Schroeder A, et al. Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies. Cancer Res 2006; 66:473-81. (Pubitemid 43166056)
38. Tokarski JS, Newitt JA, Chang CY, et al. The structure of dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res 2006; 66:5790-7. (Pubitemid 43927133)
39. Giannoudis A, Davies A, Lucas CM, et al. Effective dasatinib uptake may occur without human organic cation transporter 1 (hOCT1): implications for the treatment of imatinib-resistant chronic myeloid leukemia. Blood 2008; 112:3348-54.
40. Hiwase DK, Saunders V, Hewett D, et al. Dasatinib cellular uptake and efflux in chronic myeloid leukemia cells: therapeutic implications. Clin Cancer Res 2008; 14:3881-8.
41. O'Hare T, Walters DK, Stoffregen EP, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant abl kinase domain mutants. Cancer Res 2005; 65:4500-5. (Pubitemid 40740783)
42. Cortes J, Rousselot P, Kim D-W, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 2007; 109:3207-13. (Pubitemid 46572505)
43. Hochhaus A, Baccarani M, Deininger M, et al. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in CP with resistance or intolerance to imatinib. Leukemia 2008; 22:1200-6. (Pubitemid 351833788)
44. Apperley JF, Cortes JE, Kim DW, et al. Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START A trial. J Clin Oncol 2009; 27:3472-9.
45. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed CP chronic myeloid leukemia. N Engl J Med 2010; 362:2260-70.
46. Kantarjian H, Shah NP, Cortes JE, et al. Dasatinib or imatinib (IM) in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): Two-year follow-up from DASISION. J Clin Oncol 2011; 29:abstract 6510. Available at: www.asco.org. Accessed November 18, 2011.
47. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 2005; 7:129-41. (Pubitemid 40248339)
48. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010; 362:2251-9.
49. Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed CP, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet 2011; 12:841-51.
50. Cortes JE, Kantarjian HM, Brümmendorf TH, 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.
51. Agis H, Jaeger E, Doninger B, et al. In vivo effects of imatinib mesylate on human haematopoietic progenitor cells. Eur J Clin Invest 2006; 36:402-8. (Pubitemid 43742698)
52. Irvine DA, Zhang B, Allan EK, et al. Combination of the hedgehog pathway inhibitor LDE225 and nilotinib eliminates chronic myeloid leukemia stem and progenitor cells. Blood 2009; 114:abstract 1428.
53. Hu Y, Chen Y, Douglas L, et al. beta-Catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemia. Leukemia 2009; 23:109-16.
54. Corbin AS, Agarwal A, Loriaux M, et al. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Invest 2011; 121:396-409.
55. Ross DM, Branford S, Seymour JF, et al. Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR. Leukemia 2010; 24:1719-24.
56. Chomel JC, Bonnet M-L, Sorel N, et al. Leukemic stem cell persistence in chronic myeloid leukemia patients with sustained undetectable molecular residual disease. Blood 2011; 118:3657-60.
57. Mahon FX, Réa D, Guilhot J, et al. 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; 11:1029-35.
58. Stein AM, Bottino D, Modur V, et al. BCR-ABL transcript dynamics support the hypothesis that leukemic stem cells are reduced during imatinib treatment. Clin Cancer Res 2011; 17:6812-21.
59. Tang M, Gonen M, Quintas-Cardama A, et al. Dynamics of chronic myeloid leukemia response to long-term targeted therapy reveal treatment effects on leukemic stem cells. Blood 2011; 118:1622-31.
60. Sirard C, Lapidot T, Vormoor J, et al. Normal and leukemic SCID-repopulating cells (SRC) coexist in the bone marrow and peripheral blood from CML patients in CP, whereas leukemic SRC are detected in blast crisis. Blood 1996; 87:1539-48. (Pubitemid 26056919)
61. - progenitor cells in early CP, but not in more advanced phases, of chronic myelogenous leukemia are polyclonal. Blood 1999; 93:284-92.
62. lo population in chronic myeloid leukemia: an analysis using interphase fluorescence in situ hybridization. Blood 1995; 86:737-43.
63. Jiang X, Zhao Y, Smith C, et al. Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCR-ABL targeted therapies. Leukemia 2007; 21:926-35. (Pubitemid 46672068)
64. Holyoake TL, Jiang X, Drummond MW, et al. Elucidating critical mechanisms of deregulated stem cell turnover in the CP of chronic myeloid leukemia. Leukemia 2002; 16:549-58. (Pubitemid 34449732)
65. Holyoake T, Jiang X, Eaves C, et al. Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood 1999; 94:2056-64. (Pubitemid 29430422)
66. Raaijmakers MH, Scadden DT. Evolving concepts on the microenvironmental niche for hematopoietic stem cells. Curr Opin Hematol 2008; 15:301-6.
67. Carter BZ, Mak DH, Cortes J, et al. The elusive chronic myeloid leukemia stem cell: does it matter and how do we eliminate it? Semin Hematol 2010; 47:362-70.
68. Krause DS, Lazarides K, von Andrian UH, et al. Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells. Nat Med 2006; 12:1175-80. (Pubitemid 44527353)
69. Sloma I, Jiang X, Eaves AC, et al. Insights into the stem cells of chronic myeloid leukemia. Leukemia 2010; 24:1823-33.
70. Petzer AL, Eaves CJ, Barnett MJ, et al. Selective expansion of primitive normal hematopoietic cells in cytokine-supplemented cultures of purified cells from patients with chronic myeloid leukemia. Blood 1997; 90:64-9. (Pubitemid 27276548)
71. Udomsakdi C, Eaves CJ, Swolin B, et al. Rapid decline of chronic myeloid leukemic cells in long-term culture due to a defect at the leukemic stem cell level. Proc Natl Acad Sci U S A 1992; 89:6192-6.
72. Florian S, Sonneck K, Hauswirth AW, et al. Detection of molecular targets on the surface of CD34+/CD38- stem cells in various myeloid malignancies. Leuk Lymphoma 2006; 47:207-22. (Pubitemid 43084559)
73. Eppert K, Takenaka K, Lechman ER, et al. Stem cell gene expression programs influence clinical outcome in human leukemia. Nat Med 2011; 17:1086-94.
74. Wu Y, Zhang X, Salmon M, et al. TGFbeta1 regulation of vimentin gene expression during differentiation of the C2C12 skeletal myogenic cell line requires Smads, AP-1 and Sp1 family members. Biochim Biophys Acta 2007; 1773:427-39.
75. Diaz-Blanco E, Bruns I, Neumann F, et al. Molecular signature of CD34(+) hematopoietic stem and progenitor cells of patients with CML in CP. Leukemia 2007; 21:494-504.
76. Rizo A, Horton SJ, Olthof S, et al. BMI1 collaborates with BCR-ABL in leukemic transformation of human CD34+ cells. Blood 2010; 116:4621-30.
77. Mohty M, Yong AS, Szydlo RM, et al. The polycomb group BMI1 gene is a molecular marker for predicting prognosis of chronic myeloid leukemia. Blood 2007; 110:380-3. (Pubitemid 47026858)
78. Palamà IE, Leporatti S, de Luca E, et al. Imatinib-loaded polyelectrolyte microcapsules for sustained targeting of BCR-ABL+ leukemia stem cells. Nanomedicine (Lond) 2010; 5:419-31.
79. Naka K, Hoshii T, Muraguchi T, et al. TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature 2010; 463:676-80.
80. Jamieson CH, Ailles LE, Dylla SJ, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 2004; 351:657-67. (Pubitemid 39063268)
81. Zhao C, Blum J, Chen A, et al. Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell 2007; 12:528-41. (Pubitemid 350199070)
82. Peterson LF, Turbiak AJ, Giannola DM, et al. Wnt pathway-directed compound targets blast crisis and CP CML leukemia stem progenitors. Blood 2009; 114:abstract 2168.
83. Nagao R, Kimura S, Ashihara E, et al. A novel b-catenin inhibitor, AV65 suppresses the growth of CML cell lines which acquire imatinib-resistance because of Abl kinase domain mutations including T315I and hypoxia-adaptation. Blood 2008; 112:abstract 1081.
84. Nagao R, Ashihara E, Kimura S, et al. Inhibition of Wnt/β-catenin signaling by AV65 treatment caused cell cycle arrest and induced caspase-independent or -dependent apoptosis in CML cells. Blood 2009; 114:abstract 2184.
85. Gregory MA, Phang TL, Neviani P, et al. Wnt/Ca2+/NFAT signaling maintains survival of Ph+ leukemia cells upon inhibition of Bcr-Abl. Cancer Cell 2010; 18:74-87.
86. Muller MR, Rao A. NFAT, immunity and cancer: a transcription factor comes of age. Nat Rev Immunol 2010; 10:645-56.
87. Burgess GS, Williamson EA, Cripe LD, et al. Regulation of the c-jun gene in p210 BCR-ABL transformed cells corresponds with activity of JNK, the c-jun N-terminal kinase. Blood 1998; 92:2450-60. (Pubitemid 28452988)
88. Gupta S, Takebe N, LoRusso P. Targeting the hedgehog pathway in cancer. Ther Adv Med Oncol 2010; 2:237-50.
89. Dierks C, Beigi R, Guo GR, et al. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on hedgehog pathway activation. Cancer Cell 2008; 14:238-49.
90. Lin TL, Wang QH, Brown P, et al. Self-renewal of acute lymphocytic leukemia cells is limited by the hedgehog pathway inhibitors cyclopamine and IPI-926. PLoS ONE 2010; 5: e15262.
91. Long B, Zhu H, Zhu C, et al. Activation of the hedgehog pathway in chronic myelogeneous leukemia patients. J Exp Clin Cancer Res 2011; 30:8.
92. Zhao C, Chen A, Jamieson CH, et al. Hedgehog signaling is essential for maintenance of cancer stem cells in myeloid leukemia. Nature 2009; 458:776-9.
93. Siu LL, Papadopoulos K, Alberts SR, et al. A first-in-human, phase I study of an oral hedgehog (HH) pathway antagonist, BMS-833923 (XL139), in subjects with advanced or metastatic solid tumors. J Clin Oncol 2010; 28:2501.
94. LoRusso PM, Rudin CM, Reddy JC, et al. Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res 2011; 17:2502-11.
95. Rudin CM, Hann CL, Laterra J, et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med 2009; 361:1173-8.
96. Stuetz AA, de Rie MAC, Skvara HB, et al. FC24 LDE225, a specific smoothened inhibitor, for the topical treatment of nevoid basal cell carcinoma syndrome (Gorlin's syndrome). Melanoma Res 2010; 20:e40.
97. Ahnert RJ, Baselga J, Tawbi HA, et al. A phase I dose-escalation study of LDE225, a smoothened (SMO) antagonist, in patients with advanced solid tumors. J Clin Oncol 2010; 28 (suppl):abstract 2500. Available at: www.asco.org. Accessed November 18, 2011.
98. Melnick A, Licht JD. Histone deacetylases as therapeutic targets in hematologic malignancies. Curr Opin Hematol 2002; 9:322-32. (Pubitemid 34596877)
99. Zhang B, Strauss AC, Chu S, et al. Effective targeting of quiescent chronic myelogenous leukemia stem cells by histone deacetylase inhibitors in combination with imatinib mesylate. Cancer Cell 2010; 17:427-42.
100. Fiskus W, Pranpat M, Balasis M, et al. Cotreatment with vorinostat (suberoylanilide hydroxamic acid) enhances activity of dasatinib (BMS-354825) against imatinib mesylate-sensitive or imatinib mesylate-resistant chronic myelogenous leukemia cells. Clin Cancer Res 2006; 12:5869-78. (Pubitemid 44629620)
101. Fiskus W, Pranpat M, Bali P, et al. Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against Bcr-Abl-expressing human leukemia cells. Blood 2006; 108:645-52. (Pubitemid 44061366)
102. Nimmanapalli R, Fuino L, Stobaugh C, et al. Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl-positive human acute leukemia cells. Blood 2003; 101:3236-9. (Pubitemid 36858020)
103. Nimmanapalli R, Fuino L, Bali P, et al. Histone deacetylase inhibitor LAQ824 both lowers expression and promotes proteasomal degradation of Bcr-Abl and induces apoptosis of imatinib mesylate-sensitive or -refractory chronic myelogenous leukemia-blast crisis cells. Cancer Res 2003; 63:5126-35. (Pubitemid 37022654)
104. Dai Y, Chen S, Venditti CA, et al. Vorinostat synergistically potentiates MK-0457 lethality in chronic myelogenous leukemia (CML) cells sensitive and resistant to imatinib mesylate. Blood 2008; 112:793-804.
105. Weisberg E, Catley L, Kujawa J, et al. Histone deacetylase inhibitor NVP-LAQ824 has significant activity against myeloid leukemia cells in vitro and in vivo. Leukemia 2004; 18:1951-63. (Pubitemid 40028421)
106. Bali P, Pranpat M, Bradner J, et al. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J Biol Chem 2005; 280:26729-34. (Pubitemid 41040705)
107. Strauss AC, Chu S, Holyoake T, et al. Effective induction of apoptosis in chronic myeloid leukemia CD34+ cells by the histone deacetylase inhibitor LAQ824 in combination with imatinib. Blood 2007; 110:1031.
108. Wang Y, Fiskus W, Chong DG, et al. Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells. Blood 2009; 114:5024-33.
109. Fiskus W, Buckley K, Rao R, et al. Panobinostat treatment depletes EZH2 and DNMT1 levels and enhances decitabine mediated de-repression of JunB and loss of survival of human acute leukemia cells. Cancer Biol Ther 2009; 8:939-50.
110. Deng T, Karin M. JunB differs from c-Jun in its DNA-binding and dimerization domains, and represses c-Jun by formation of inactive heterodimers. Genes Dev 1993; 7:479-90. (Pubitemid 23139240)
111. Passegué E, Wagner EF, Weissman IL. JunB deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells. Cell 2004; 119:431-43. (Pubitemid 39423844)
112. Issa J-PJ, Gharibyan V, Cortes J, et al. Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate. J Clin Oncol 2005; 23:3948-56. (Pubitemid 46218698)
113. Kalle AM, Sachchidanand S, Pallu R. Bcr-Abl-independent mechanism of resistance to imatinib in K562 cells: induction of cyclooxygenase-2 (COX-2) by histone deacetylases (HDACs). Leuk Res 2010; 34:1132-8.
114. Ottmann OG, Spencer A, Prince HM, et al. Phase IA/II study of oral panobinostat (LBH589), a novel pan-deacetylase inhibitor (DACi) demonstrating efficacy in patients with advanced hematologic malignancies. Blood 2008; 112:abstract 958.
115. Bhatia R, Snyder DS, Lin A, et al. A phase I study of the HDAC inhibitor LBH589 in combination with imatinib for patients with CML in cytogenetic remission with residual disease detectable by Q-PCR. Blood 2009; 114:abstract 2194.
116. International Clinical Trials Registry Platform. Dasatinib and vorinostat in treating patients with accelerated phase or blastic phase chronic myelogenous leukemia or acute lymphoblastic leukemia [Identifier NCT00816283].Available at: http://apps.who.int/trialsearch/trial.aspx?trialid= NCT00816283. Accessed May 18, 2011.
117. Chen Y, Hu Y, Michaels S, et al. Inhibitory effects of omacetaxine on leukemic stem cells and BCR-ABL-induced chronic myeloid leukemia and acute lymphoblastic leukemia in mice. Leukemia 2009; 23:1446-54.
118. O'Brien S, Kantarjian H, Keating M, et al. Homoharringtonine therapy induces responses in patients with chronic myelogenous leukemia in late CP. Blood 1995; 86:3322-6.
119. O'Brien S, Talpaz M, Cortes J, et al. Simultaneous homoharringtonine and interferon-alpha in the treatment of patients with chronic-phase chronic myelogenous leukemia. Cancer 2002; 94:2024-32. (Pubitemid 34270056)
120. Kantarjian HM, Talpaz M, Smith TL, et al. Homoharringtonine and low-dose cytarabine in the management of late chronic-phase chronic myelogenous leukemia. J Clin Oncol 2000; 18:3513-21.
121. O'Brien S, Giles F, Talpaz M, et al. Results of triple therapy with interferon-alpha, cytarabine, and homoharringtonine, and the impact of adding imatinib to the treatment sequence in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in early CP. Cancer 2003; 98:888-93. (Pubitemid 37022086)
122. Marin D, Kaeda JS, Andreasson C, et al. Phase I/II study of adding semisynthetic homoharringtonine in chronic myeloid leukemia patients who have achieved partial or complete cytogenetic response on imatinib. Cancer 2005; 103:1850-5. (Pubitemid 40563257)
123. Quintás-Cardama A, Kantarjian H, Garcia-Manero G, et al. Phase I/II study of subcutaneous homoharringtonine in patients with chronic myeloid leukemia who have failed prior therapy. Cancer 2007; 109:248-55. (Pubitemid 46106239)
124. Cortes-Franco J, Khoury J, Nicolini FE, et al. Safety and efficacy of subcutaneous-administered omacetaxine mepesuccinate in imatinib-resistant chronic myeloid leukemia (CML) patients who harbor the Bcr- Abl T315I mutation-results of an ongoing multicenter phase 2/3 study. Blood 2009; 114:abstract 644.
125. Aichberger KJ, Mayerhofer M, Krauth MT, et al. Identification of mcl-1 as a BCR/ABL-dependent target in chronic myeloid leukemia (CML): evidence for cooperative antileukemic effects of imatinib and mcl-1 antisense oligonucleotides. Blood 2005; 105:3303-11.
126. Kuroda J, Puthalakath H, Cragg MS, et al. Bim and Bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic. Proc Natl Acad Sci U S A 2006; 103:14907-12. (Pubitemid 44527827)
127. Lou YJ, Jin J. Triptolide down-regulates bcr-abl expression and induces apoptosis in chronic myelogenous leukemia cells. Leuk Lymphoma 2004; 45:373-6. (Pubitemid 38181443)
128. Mak DH, Schober WD, Chen W et al. Triptolide induces cell death independent of cellular responses to imatinib in blast crisis chronic myelogenous leukemia cells including quiescent CD34+ primitive progenitor cells. Mol Cancer Ther 2009; 8:2509-16.
129. Shi X, Jin Y, Cheng C, et al. Triptolide inhibits Bcr-Abl transcription and induces apoptosis in STI571-resistant chronic myelogenous leukemia cells harboring T315I mutation. Clin Cancer Res 2009; 15:1686-97.
130. Kuroda J, Kimura S, Andreeff M, et al. ABT-737 is a useful component of combinatory chemotherapies for chronic myeloid leukaemias with diverse drug-resistance mechanisms. Br J Haematol 2008; 140:181-90. (Pubitemid 350265045)
131. L Promotes apoptosis in blast crisis CML including quiescent primitive progenitor cells regardless of cellular responses to tyrosine kinase inhibitors. Blood 2009; 114:abstract 646.
132. Ito K, Bernardi R, Morotti A, et al. PML targeting eradicates quiescent leukemia-initiating cells. Nature 2008; 453:1072-8. (Pubitemid 351871736)
133. Chen Y, Hu Y, Zhang H, et al. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nat Genet 2009; 41:783-92.
134. International Clinical Trials Registry Platform. Safety of zileuton (Zyflo) in combination with imatinib mesylate (Gleevec) in CML [Identifier NCT01130688]. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01130688. Accessed May 18, 2011.
135. Mayer IA, Verma A, Grumbach IM, et al. The p38 MAPK pathway mediates the growth inhibitory effects of interferon-alpha in BCR-ABL-expressing cells. J Biol Chem 2001; 276:28570-7.
136. Saydam G, Aydin HH, Sahin F, et al. Involvement of protein phosphatase 2A in interferon-alpha-2b-induced apoptosis in K562 human chronic myelogenous leukaemia cells. Leuk Res 2003; 27:709-17. (Pubitemid 36683260)
137. Parmar S, Smith J, Sassano A, et al. Differential regulation of the p70 S6 kinase pathway by interferon alpha (IFNalpha) and imatinib mesylate (STI571) in chronic myelogenous leukemia cells. Blood 2005; 106:2436-43. (Pubitemid 41510818)
138. Angstreich GR, Matsui W, Huff CA, et al. Effects of imatinib and interferon on primitive chronic myeloid leukaemia progenitors. Br J Haematol 2005; 130:373-81. (Pubitemid 43899585)
139. Rousselot P, Huguet F, Rea D, et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood 2007; 109:58-60. (Pubitemid 46053043)
140. Hochhaus A, Reiter A, Saussele S, et al. Molecular heterogeneity in complete cytogenetic responders after interferon-alpha therapy for chronic myelogenous leukemia: low levels of minimal residual disease are associated with continuing remission. German CML Study Group and the UK MRC CML Study Group. Blood 2000; 95:62-6. (Pubitemid 30017225)
141. Essers MA, Offner S, Blanco-Bose WE, et al. IFNalpha activates dormant haematopoietic stem cells in vivo. Nature 2009; 458:904-8.
142. Sato T, Onai N, Yoshihara H, et al. Interferon regulatory factor-2 protects quiescent hematopoietic stem cells from type I interferon-dependent exhaustion. Nat Med 2009; 15:696-700.
143. Palandri F, Castagnetti F, Iacobucci I, et al. The response to imatinib and interferon-alpha is more rapid than the response to imatinib alone: a retrospective analysis of 495 Philadelphia-positive chronic myeloid leukemia patients in early CP. Haematologica 2010; 95:1415-9.
144. Preudhomme C, Guilhot J, Nicolini FE, et al. Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med 2010; 363:2511-21.
145. Burchert A, Müller MC, Kostrewa P, et al. Sustained molecular response with interferon alfa maintenance after induction therapy with imatinib plus interferon alfa in patients with chronic myeloid leukemia. J Clin Oncol 2010; 28:1429-35.
146. O'Shea JJ, Gadina M, Schreiber RD. Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell 2002; 109:S121-31. (Pubitemid 34457857)
147. Rane SG, Reddy EP. JAKs, STATs and Src kinases in hematopoiesis. Oncogene 2002; 21:3334-58. (Pubitemid 34587707)
148. Xie S, Wang Y, Liu J, et al. Involvement of Jak2 tyrosine phosphorylation in Bcr-Abl transformation. Oncogene 2001; 20:6188-95. (Pubitemid 32964431)
149. Xie S, Lin H, Sun T, et al. Jak2 is involved in c-Myc induction by Bcr-Abl. Oncogene 2002; 21:7137-46. (Pubitemid 35305600)
150. Samanta AK, Lin H, Sun T, et al. Janus kinase 2: a critical target in chronic myelogenous leukemia. Cancer Res 2006; 66:6468-72. (Pubitemid 44085597)
151. Zhou LL, Zhao Y, Ringrose A, et al. AHI-1 interacts with BCR-ABL and modulates BCR-ABL transforming activity and imatinib response of CML stem/progenitor cells. J Exp Med 2008; 205:2657-71.
152. Jatiani SS, Cosenza SC, Reddy MV, et al. A non-ATP-competitive dual inhibitor of JAK2 and BCR-ABL kinases: elucidation of a novel therapeutic spectrum based on substrate competitive inhibition. Genes Cancer 2010; 1:331-45.
153. Samanta AK, Chakraborty SN, Wang Y, et al. Destabilization of Bcr-Abl/Jak2 network by a Jak2/Abl kinase inhibitor ON044580 overcomes drug resistance in blast crisis chronic myelogenous leukemia (CML). Genes Cancer 2010; 1:346-59.
154. DeGeer D, Newmarch K, Zhou L, et al. A Novel AHI-1-BCR-ABL-JAK2 interaction complex mediates cellular resistance to tyrosine kinase inhibitors in CML. Blood 2009; 114:abstract 38.
155. An WG, Schulte TW, Neckers LM. The heat shock protein 90 antagonist geldanamycin alters chaperone association with p210bcr-abl and v-src proteins before their degradation by the proteasome. Cell Growth Differ 2000; 11:355-60. (Pubitemid 30619563)
156. Bansal H, Bansal S, Rao M, et al. Heat shock protein 90 regulates the expression of Wilms' tumor 1 protein in myeloid leukemias. Blood 2010; 116:4591-9.
157. Gerber JM, Qin L, Kowalski J, et al. Characterization of chronic myeloid leukemia stem cells. Am J Hematol 2011; 86:31-7.
158. Otahalova E, Ullmannova-Benson V, Klamova H, et al. WT1 expression in peripheral leukocytes of patients with chronic myeloid leukemia serves for the prediction of imatinib resistance. Neoplasma 2009; 56:393-7.
159. Varma N, Anand MS, Varma S, et al. Role of hTERT and WT1 gene expression in disease progression and imatinib responsiveness of patients with BCR-ABL positive chronic myeloid leukemia. Leuk Lymphoma 2011; 52:687-93.
160. Nimmanapalli R, O'Bryan E, Bhalla K. 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 2001; 61:1799-804. (Pubitemid 32691987)
161. Ge J, Normant E, Porter JR, et al. Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90. J Med Chem 2006; 49:4606-15. (Pubitemid 44162687)
162. Peng C, Brain J, Hu Y, et al. Inhibition of heat shock protein 90 prolongs survival of mice with BCR-ABL-T315I-induced leukemia and suppresses leukemia stem cells. Blood 2007; 110:678-85. (Pubitemid 47105407)
163. ClinicalTrials.gov. A phase 1/2 study of the HSP90 inhibitor, STA-9090, administered once-weekly in subjects with acute myeloid leukemia, acute lymphoblastic leukemia and blast-phase chronic myelogenous leukemia [Identifier NCT00964873]. Available at: http://clinicaltrials.gov/ct2/show/NCT00964873. Accessed May 18, 2011.
164. Tauchi T, Okabe S, Ashihara E, et al. Combined effects of novel heat shock protein 90 inhibitor NVP-AUY922 and nilotinib in a random mutagenesis screen. Oncogene 2011; 30:2789-97.
165. Beck R, Dejeans N, Glorieux C, et al. Molecular chaperone hsp90 as a target for oxidant-based anticancer therapies. Curr Med Chem 2011; 18:2816-25.
166. ClinicalTrials.gov. Dasatinib combined with SMO inhibitor (BMS-833923; XL 139) in CML with resistance or suboptimal response to a prior TKI [Identifier NCT01218477]., Available at: http://clinicaltrials.gov/ct2/show/NCT01218477. Accessed May 18, 2011.
167. ClinicalTrials.gov. A phase 1 study to evaluate the safety, pharmacokinetics, and pharmacodynamics of PF-04449913, an oral Hedgehog inhibitor, administered as single agent in select hematologic malignancies or in combination with dasatinib or bosutinib in chronic myeloid leukemia (CML) [Identifier NCT00953758]. Available at: http://clinicaltrials.gov/ct2/show/ NCT00953758. Accessed September 13, 2011.
168. International Clinical Trials Registry Platform. Homoharringtonine with oral Gleevec in chronic, accelerated and blast phase chronic myeloid leukemia (CML) [Identifier NCT00114959]. Available at: http://apps.who.int/trialsearch/ trial.aspx?trialid=NCT00114959. Accessed May 18, 2011.
169. Hoover RR, Mahon F-X, Melo JV, et al. Overcoming STI571 resistance with the farnesyl transferase inhibitor SCH66336. Blood 2002; 100:1068-71. (Pubitemid 34832641)
170. Jorgensen HG, Allan EK, Graham SM, et al. Lonafarnib reduces the resistance of primitive quiescent CML cells to imatinib mesylate in vitro. Leukemia 2005; 19:1184-91. (Pubitemid 40946002)
171. Cortes J, Jabbour E, Daley GQ, et al. Phase 1 study of lonafarnib (SCH 66336) and imatinib mesylate in patients with chronic myeloid leukemia who have failed prior single-agent therapy with imatinib. Cancer 2007; 110:1295-302. (Pubitemid 47435601)
172. Cortes J, Quintás-Cardama A, Garcia-Manero G, et al. Phase 1 study of tipifarnib in combination with imatinib for patients with chronic myelogenous leukemia in CP after imatinib failure. Cancer 2007; 110:2000-6. (Pubitemid 350036859)