Critical molecular pathways in cancer stem cells of chronic myeloid leukemia

Leukemia

Volumn 24, Issue 9, 2010, Pages 1545-1554

  Chen, Y ^a   Peng, C ^a   Sullivan, C ^b   Li, D ^c   Li, S ^a  

^a UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL   (United States)

^b Maine Institute for Human Genetics & Health   (United States)

^c EDITH COWAN UNIVERSITY   (Australia)

Author keywords

BCR ABL; CML; leukemic stem cells; therapeutic agents

Indexed keywords

3 BENZYL 7 CYANO 2,3,4,5 TETRAHYDRO 1 (1H IMIDAZOL 4 YLMETHYL) 4 (2 THIENYLSULFONYL) 1H 1,4 BENZODIAZEPINE; ALPHA INTERFERON; BCR ABL PROTEIN; BETA CATENIN; BORTEZOMIB; BRYOSTATIN 1; CYCLOPAMINE; DASATINIB; FINGOLIMOD; HOMOHARRINGTONINE; IMATINIB; OMACETAXINE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN; PROTEIN FOX O; SONIC HEDGEHOG PROTEIN; TANESPIMYCIN HYDROQUINONE; UNCLASSIFIED DRUG; WNT PROTEIN; ZILEUTON; ANTINEOPLASTIC AGENT; PROTEIN KINASE INHIBITOR;

CANCER STEM CELL; CELL STRUCTURE; CHRONIC MYELOID LEUKEMIA; COLONY FORMING UNIT GM; DRUG EFFECT; DRUG TREATMENT FAILURE; HEMATOPOIETIC STEM CELL; HUMAN; MANTLE CELL LYMPHOMA; MOLECULAR DYNAMICS; MULTIPLE MYELOMA; NONHUMAN; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN EXPRESSION; REVIEW; SIGNAL TRANSDUCTION; TARGET CELL; ANIMAL; DISEASE MODEL; LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE; MOUSE; MUTATION; ONCOGENE; PATHOLOGY; TRANSGENIC MOUSE;

ANIMALS; ANTINEOPLASTIC AGENTS; DISEASE MODELS, ANIMAL; GENES, ABL; HUMANS; LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE; MICE; MICE, TRANSGENIC; MUTATION; NEOPLASTIC STEM CELLS; PROTEIN KINASE INHIBITORS;

EID: 77956440189     PISSN: 08876924     EISSN: 14765551     Source Type: Journal    
DOI: 10.1038/leu.2010.143     Document Type: Review

References (118)

1. Mughal TI, Yong A, Szydlo RM, Dazzi F, Olavarria E, van Rhee F et al. Molecular studies in patients with chronic myeloid leukaemia in remission 5 years after allogeneic stem cell transplant define the risk of subsequent relapse. Br J Haematol 2001; 115: 569-574.
2. Goldman J. Allogeneic stem cell transplantation for chronic myeloid leukemiaFstatus in 2007. Bone Marrow Transplant 2008; 42 (Suppl 1): S11-S13.
3. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001; 344: 1038-1042.
4. Druker BJ, Guilhot F, OBrien SG, Gathmann I, Kantarjian H, Gattermann N et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006; 355: 2408-2417. (Pubitemid 44903745)
5. Bhatia R, Holtz M, Niu N, Gray R, Snyder DS, Sawyers CL et al. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 2003; 101: 4701-4707.
6. Rousselot P, Huguet F, Rea D, Legros L, Cayuela JM, Maarek O 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.
7. 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: 876-880.
8. Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2002; 2: 117-125.
9. Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 2002; 99: 319-325.
10. Hu Y, Swerdlow S, Duffy TM, Weinmann R, Lee FY, Li S. Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice. Proc Natl Acad Sci USA 2006; 103: 16870-16875.
11. Hu Y, Chen Y, Douglas L, Li S. 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: 109-116.
12. Graham SM, Vass JK, Holyoake TL, Graham GJ. Transcriptional analysis of quiescent and proliferating CD34+ human hemopoietic cells from normal and chronic myeloid leukemia sources. Stem Cell (Dayton, Ohio) 2007; 25: 3111-3120.
13. Radich JP, Dai H, Mao M, Oehler V, Schelter J, Druker B et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci USA 2006; 103: 2794-2799.
14. Bruns I, Czibere A, Fischer JC, Roels F, Cadeddu RP, Buest S et al. The hematopoietic stem cell in chronic phase CML is characterized by a transcriptional profile resembling normal myeloid progenitor cells and reflecting loss of quiescence. Leukemia 2009; 23: 892-899.
15. Goldman JM, Green AR, Holyoake T, Jamieson C, Mesa R, Mughal T et al. Chronic myeloproliferative diseases with and without the Ph chromosome: some unresolved issues. Leukemia 2009; 23: 1708-1715.
16. Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 1990; 247: 824-830.
17. Kelliher MA, McLaughlin J, Witte ON, Rosenberg N. Induction of a chronic myelogenous leukemia-like syndrome in mice with v-abl and BCR/ABL. Proc Natl Acad Sci USA 1990; 87: 6649-6653.
18. Elefanty AG, Hariharan IK, Cory S. bcr-abl, the hallmark of chronic myeloid leukaemia in man, induces multiple haemopoietic neoplasms in mice. EMBO J 1990; 9: 1069-1078.
19. Pear WS, Miller JP, Xu L, Pui JC, Soffer B, Quackenbush RC et al. Efficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receiving P210 bcr/abl-transduced bone marrow. Blood 1998; 92: 3780-3792.
20. Zhang X, Ren R. Bcr-Abl efficiently induces a myeloproliferative disease and production of excess interleukin-3 and granulocyte-macrophage colony-stimulating factor in mice: a novel model for chronic myelogenous leukemia. Blood 1998; 92: 3829-3840.
21. Li S, Ilaria Jr RL, Million RP, Daley GQ, Van Etten RA. The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activity. J Exp Med 1999; 189: 1399-1412.
22. Chen Y, Hu Y, Zhang H, Peng C, Li S. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nat Genet 2009; 41: 783-792.
23. Heisterkamp N, Jenster G, ten Hoeve J, Zovich D, Pattengale PK, Groffen J. Acute leukaemia in bcr/abl transgenic mice. Nature 1990; 344: 251-253.
24. Honda H, Oda H, Suzuki T, Takahashi T, Witte ON, Ozawa K et al. Development of acute lymphoblastic leukemia and myeloproliferative disorder in transgenic mice expressing p210bcr/abl: a novel transgenic model for human Ph1-positive leukemias. Blood 1998; 91: 2067-2075.
25. Huettner CS, Zhang P, Van Etten RA, Tenen DG. Reversibility of acute B-cell leukaemia induced by BCR-ABL1. Nat Genet 2000; 24: 57-60.
26. Koschmieder S, Gottgens B, Zhang P, Iwasaki-Arai J, Akashi K, Kutok JL et al. Inducible chronic phase of myeloid leukemia with expansion of hematopoietic stem cells in a transgenic model of BCR-ABL leukemogenesis. Blood 2005; 105: 324-334.
27. Wang JC, Lapidot T, Cashman JD, Doedens M, Addy L, Sutherland DR et al. High level engraftment of NOD/SCID mice by primitive normal and leukemic hematopoietic cells from patients with chronic myeloid leukemia in chronic phase. Blood 1998; 91: 2406-2414.
28. Holyoake T, Jiang X, Eaves C, Eaves A. Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood 1999; 94: 2056-2064.
29. Copland M, Pellicano F, Richmond L, Allan EK, Hamilton A, Lee FY et al. BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors. Blood 2008; 111: 2843-2853.
30. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100: 3983-3988. (Pubitemid 36418143)
31. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med 2006; 355: 1253-1261.
32. Pardal R, Clarke MF, Morrison SJ. Applying the principles of stemcell biology to cancer. Nat Rev Cancer 2003; 3: 895-902.
33. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001; 414: 105-111.
34. Rossi DJ, Jamieson CH, Weissman IL. Stems cells and the pathways to aging and cancer. Cell 2008; 132: 681-696.
35. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003; 63: 5821-5828.
36. Wang JC, Dick JE. Cancer stem cells: lessons from leukemia. Trends Cell Biol 2005; 15: 494-501.
37. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres- Cortes J et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994; 367: 645-648.
38. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3: 730-737.
39. Park CY, Tseng D, Weissman IL. Cancer stem cell-directed therapies: recent data from the laboratory and clinic. Mol Ther 2009; 17: 219-230.
40. Maguer-Satta V, Petzer AL, Eaves AC, Eaves CJ. BCR-ABL expression in different subpopulations of functionally characterized Ph+ CD34+ cells from patients with chronic myeloid leukemia. Blood 1996; 88: 1796-1804.
41. Macchiarini F, Manz MG, Palucka AK, Shultz LD. Humanized mice: are we there yet? J Exp Med 2005; 202: 1307-1311.
42. Jamieson CH, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 2004; 351: 657-667.
43. Minami Y, Stuart SA, Ikawa T, Jiang Y, Banno A, Hunton IC et al. BCR-ABL-transformed GMP as myeloid leukemic stem cells. Proc Natl Acad Sci USA 2008; 105: 17967-17972.
44. Copland M, Hamilton A, Elrick LJ, Baird JW, Allan EK, Jordanides N 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: 4532-4539.
45. Heinrich MC, Blanke CD, Druker BJ, Corless CL. Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol 2002; 20: 1692-1703.
46. Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 2003; 423: 409-414.
47. Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S, Kikuchi A. Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK- 3beta-dependent phosphorylation of beta-catenin. EMBO J 1998; 17: 1371-1384.
48. Aberle H, Bauer A, Stappert J, Kispert A, Kemler R. Beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J 1997; 16: 3797-3804.
49. Zhao C, Blum J, Chen A, Kwon HY, Jung SH, Cook JM et al. Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell 2007; 12: 528-541.
50. Wang Y, Krivtsov AV, Sinha AU, North TE, Goessling W, Feng Z et al. The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science 2010; 327: 1650-1653.
51. Nusslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature 1980; 287: 795-801.
52. Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, McMahon JA et al. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 1993; 75: 1417-1430.
53. Chang DT, Lopez A, von Kessler DP, Chiang C, Simandl BK, Zhao R et al. Products, genetic linkage and limb patterning activity of a murine hedgehog gene. Development (Cambridge, England) 1994; 120: 3339-3353.
54. Roelink H, Augsburger A, Heemskerk J, Korzh V, Norlin S, Ruiz i Altaba A et al. Floor plate and motor neuron induction by vhh-1, a vertebrate homolog of hedgehog expressed by the notochord. Cell 1994; 76: 761-775.
55. Yang L, Xie G, Fan Q, Xie J. Activation of the hedgehog-signaling pathway in human cancer and the clinical implications. Oncogene 2010; 29: 469-481.
56. Lee J, Platt KA, Censullo P, Ruiz i Altaba A. Gli1 is a target of Sonic hedgehog that induces ventral neural tube development. Development (Cambridge, England) 1997; 124: 2537-2552.
57. Marigo V, Tabin CJ. Regulation of patched by sonic hedgehog in the developing neural tube. Proc Natl Acad Sci USA 1996; 93: 9346-9351.
58. Dyer MA, Farrington SM, Mohn D, Munday JR, Baron MH. Indian hedgehog activates hematopoiesis and vasculogenesis and can respecify prospective neurectodermal cell fate in the mouse embryo. Development (Cambridge, England) 2001; 128: 1717-1730.
59. Gering M, Patient R. Hedgehog signaling is required for adult blood stem cell formation in zebrafish embryos. Dev Cell 2005; 8: 389-400.
60. Bitgood MJ, Shen L, McMahon AP. Sertoli cell signaling by Desert hedgehog regulates the male germline. Curr Biol 1996; 6: 298-304.
61. Byrd N, Becker S, Maye P, Narasimhaiah R, St-Jacques B, Zhang X et al. Hedgehog is required for murine yolk sac angiogenesis. Development (Cambridge, England) 2002; 129: 361-372.
62. Goodrich LV, Scott MP. Hedgehog and patched in neural development and disease. Neuron 1998; 21: 1243-1257.
63. Tostar U, Malm CJ, Meis-Kindblom JM, Kindblom LG, Toftgard R, Unden AB. Deregulation of the hedgehog signalling pathway: a possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development. J Pathol 2006; 208: 17-25.
64. Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C et al. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 1998; 391: 90-92.
65. Dierks C, Beigi R, Guo GR, Zirlik K, Stegert MR, Manley P et al. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell 2008; 14: 238-249.
66. Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 2009; 458: 776-779.
67. Catalano A, Rodilossi S, Caprari P, Coppola V, Procopio A. 5-Lipoxygenase regulates senescence-like growth arrest by promoting ROS-dependent p53 activation. EMBO J 2005; 24: 170-179.
68. Chen XS, Sheller JR, Johnson EN, Funk CD. Role of leukotrienes revealed by targeted disruption of the 5-lipoxygenase gene. Nature 1994; 372: 179-182.
69. Radmark O, Werz O, Steinhilber D, Samuelsson B. 5-Lipoxygenase: regulation of expression and enzyme activity. Trends Biochem Sci 2007; 32: 332-341.
70. Soberman RJ, Christmas P. The organization and consequences of eicosanoid signaling. J Clin Invest 2003; 111: 1107-1113.
71. Taylor PM, Woodfield RJ, Hodgkin MN, Pettitt TR, Martin A, Kerr DJ et al. Breast cancer cell-derived EMMPRIN stimulates fibroblast MMP2 release through a phospholipase A(2) and 5-lipoxygenase catalyzed pathway. Oncogene 2002; 21: 5765-5772.
72. Wymann MP, Schneiter R. Lipid signalling in disease. Nat Rev Mol Cell Biol 2008; 9: 162-176.
73. Yokomizo T, Izumi T, Shimizu T. Leukotriene B4: metabolism and signal transduction. Arch Biochem Biophys 2001; 385: 231-241.
74. Zhao L, Moos MP, Grabner R, Pedrono F, Fan J, Kaiser B et al. The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm. Nat Med 2004; 10: 966-973.
75. Peters-Golden M, Henderson Jr WR. Leukotrienes. N Engl J Med 2007; 357: 1841-1854.
76. Takayama H, Okuma M, Kanaji K, Sugiyama T, Sensaki S, Uchino H. Altered arachidonate metabolism by leukocytes and platelets in myeloproliferative disorders. Prostagland Leukot Med 1983; 12: 261-272.
77. Anderson KM, Seed T, Jajeh A, Dudeja P, Byun T, Meng J et al. An in vivo inhibitor of 5-lipoxygenase, MK886, at micromolar concentration induces apoptosis in U937 and CML cells. Anticancer Res 1996; 16: 2589-2599.
78. Anderson KM, Seed T, Plate JM, Jajeh A, Meng J, Harris JE. Selective inhibitors of 5-lipoxygenase reduce CML blast cell proliferation and induce limited differentiation and apoptosis. Leuk Res 1995; 19: 789-801.
79. Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 2007; 448: 439-444
80. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997; 275: 1943-1947.
81. Peiffer SL, Herzog TJ, Tribune DJ, Mutch DG, Gersell DJ, Goodfellow PJ. Allelic loss of sequences from the long arm of chromosome 10 and replication errors in endometrial cancers. Cancer Res 1995; 55: 1922-1926.
82. Gronbaek K, Zeuthen J, Guldberg P, Ralfkiaer E, Hou-Jensen K. Alterations of the MMAC1/PTEN gene in lymphoid malignancies. Blood 1998; 91: 4388-4390.
83. Rameh LE, Cantley LC. The role of phosphoinositide 3-kinase lipid products in cell function. J Biol Chem 1999; 274: 8347-8350.
84. Covey TM, Edes K, Fitzpatrick FA. Akt activation by arachidonic acid metabolism occurs via oxidation and inactivation of PTEN tumor suppressor. Oncogene 2007; 26: 5784-5792.
85. Peng C, Chen Y, Yang Z, Zhang H, Osterby L, Rosmarin AG et al. PTEN is a tumor suppressor in CML stem cells and BCR-ABLinduced leukemias in mice. Blood 2010; 115: 626-635.
86. Greer EL, Brunet A. FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 2005; 24: 7410-7425.
87. Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 2007; 128: 325-339.
88. Miyamoto K, Araki KY, Naka K, Arai F, Takubo K, Yamazaki S et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 2007; 1: 101-112.
89. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999; 96: 857-868.
90. Dijkers PF, Medema RH, Lammers JW, Koenderman L, Coffer PJ. Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr Biol 2000; 10: 1201-1204.
91. Kops GJ, Medema RH, Glassford J, Essers MA, Dijkers PF, Coffer PJ et al. Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors. Mol Cell Biol 2002; 22: 2025-2036.
92. Martinez-Gac L, Marques M, Garcia Z, Campanero MR, Carrera AC. Control of cyclin G2 mRNA expression by forkhead transcription factors: novel mechanism for cell cycle control by phosphoinositide 3-kinase and forkhead. Mol Cell Biol 2004; 24: 2181-2189.
93. Naka K, Hoshii T, Muraguchi T, Tadokoro Y, Ooshio T, Kondo Y et al. TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature 2010; 463: 676-680.
94. Jorgensen HG, Copland M, Allan EK, Jiang X, Eaves A, Eaves C et al. Intermittent exposure of primitive quiescent chronic myeloid leukemia cells to granulocyte-colony stimulating factor in vitro promotes their elimination by imatinib mesylate. Clin Cancer Res 2006; 12: 626-633.
95. Drummond MW, Heaney N, Kaeda J, Nicolini FE, Clark RE, Wilson G et al. A pilot study of continuous imatinib vs pulsed imatinib with or without G-CSF in CML patients who have achieved a complete cytogenetic response. Leukemia 2009; 23: 1199-1201.
96. Bellodi C, Lidonnici MR, Hamilton A, Helgason GV, Soliera AR, Ronchetti M et al. Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosomepositive cells, including primary CML stem cells. J Clin Invest 2009; 119: 1109-1123.
97. Ito K, Bernardi R, Morotti A, Matsuoka S, Saglio G, Ikeda Y et al. PML targeting eradicates quiescent leukaemia-initiating cells. Nature 2008; 453: 1072-1078.
98. Hassane DC, Guzman ML, Corbett C, Li X, Abboud R, Young F et al. Discovery of agents that eradicate leukemia stem cells using an in silico screen of public gene expression data. Blood 2008; 111: 5654-5662.
99. Nimmanapalli R, OBryan 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: 1799-1804.
100. Peng C, Brain J, Hu Y, Goodrich A, Kong L, Grayzel D et al. Inhibition of heat shock protein 90 prolongs survival of mice with BCR-ABL-T315I-induced leukemia and suppresses leukemic stem cells. Blood 2007; 110: 678-685.
101. Quintas-Cardama A, Kantarjian H, Garcia-Manero G, OBrien S, Faderl S, Estrov Z et al. Phase I/II study of subcutaneous homoharringtonine in patients with chronic myeloid leukemia who have failed prior therapy. Cancer 2007; 109: 248-255.
102. Chen Y, Hu Y, Michaels S, Segal D, Brown D, Li S. Inhibitory effects of omacetaxine on leukemic stem cells and BCR-ABLinduced chronic myeloid leukemia and acute lymphoblastic leukemia in mice. Leukemia 2009; 23: 1146-1154.
103. Legros L, Hayette S, Nicolini FE, Raynaud S, Chabane K, Magaud JP et al. BCR-ABL(T315I) transcript disappearance in an imatinibresistant CML patient treated with homoharringtonine: a new therapeutic challenge? Leukemia 2007; 21: 2204-2206.
104. Incardona JP, Gaffield W, Kapur RP, Roelink H. The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction. Development (Cambridge, England) 1998; 125: 3553-3562.
105. Chen JK, Taipale J, Cooper MK, Beachy PA. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev 2002; 16: 2743-2748.
106. Manne V, Lee FY, Bol DK, Gullo-Brown J, Fairchild CR, Lombardo LJ et al. Apoptotic and cytostatic farnesyltransferase inhibitors have distinct pharmacology and efficacy profiles in tumor models. Cancer Res 2004; 64: 3974-3980.
107. Pellicano F, Copland M, Jorgensen HG, Mountford J, Leber B, Holyoake TL. BMS-214662 induces mitochondrial apoptosis in chronic myeloid leukemia (CML) stem/progenitor cells, including CD34+38- cells, through activation of protein kinase Cbeta. Blood 2009; 114: 4186-4196.
108. Neviani P, Santhanam R, Trotta R, Notari M, Blaser BW, Liu S et al. The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABLregulated SET protein. Cancer Cell 2005; 8: 355-368.
109. Dumont FJ. Fingolimod. Mitsubishi Pharma/Novartis. IDrugs 2005; 8: 236-253.
110. Virley DJ. Developing therapeutics for the treatment of multiple sclerosis. NeuroRx 2005; 2: 638-649.
111. Neviani P, Santhanam R, Oaks JJ, Eiring AM, Notari M, Blaser BW et al. FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome- positive acute lymphocytic leukemia. J Clin Invest 2007; 117: 2408-2421.
112. Kumatori A, Tanaka K, Inamura N, Sone S, Ogura T, Matsumoto T et al. Abnormally high expression of proteasomes in human leukemic cells. Proc Natl Acad Sci USA 1990; 87: 7071-7075.
113. Magill L, Lynas J, Morris TC, Walker B, Irvine AE. Proteasome proteolytic activity in hematopoietic cells from patients with chronic myeloid leukemia and multiple myeloma. Haematologica 2004; 89: 1428-1433.
114. Cortes J, Thomas D, Koller C, Giles F, Estey E, Faderl S et al. Phase I study of bortezomib in refractory or relapsed acute leukemias. Clin Cancer Res 2004; 10: 3371-3376.
115. Gatto S, Scappini B, Pham L, Onida F, Milella M, Ball G et al. The proteasome inhibitor PS-341 inhibits growth and induces apoptosis in Bcr/Abl-positive cell lines sensitive and resistant to imatinib mesylate. Haematologica 2003; 88: 853-863.
116. Servida F, Soligo D, Delia D, Henderson C, Brancolini C, Lombardi L et al. Sensitivity of human multiple myelomas and myeloid leukemias to the proteasome inhibitor I. Leukemia 2005; 19: 2324-2331.
117. Heaney NB, Pellicano F, Zhang B, Crawford L, Chu S, Kazmi SM et al. Bortezomib induces apoptosis in primitive chronic myeloid leukemia cells including LTC-IC and NOD/SCID repopulating cells. Blood 2010; 115: 2241-2250.
118. Krause DS, Van Etten RA. Bedside to bench: interfering with leukemic stem cells. Nat Med 2008; 14: 494-495.