Targeted elimination of leukemia stem cells; a new therapeutic approach in hemato-oncology

Current Drug Targets

Volumn 11, Issue 1, 2010, Pages 95-110

  Ten Cate, B ^a   De Bruyn, M ^a   Wei, Y ^a,b   Bremer, E ^a   Helfrich, W ^a,b  

^a UNIVERSITY MEDICAL CENTER GRONINGEN   (Netherlands)

^b HARBIN MEDICAL UNIVERSITY   (China)

Author keywords

AML; Antibody; Apoptosis; CML; Epigenetics; Leukemia stem cells; Targeting

Indexed keywords

4 AMINO 6 [2 [[4 (DIETHYLAMINO) 1 METHYLBUTYL]AMINO] 6 METHYL 4 PYRIMIDINYL] 2 METHYLQUINOLINE; ANTIBODY CONJUGATE; ANTINEOPLASTIC AGENT; BCR ABL PROTEIN; BMI1 PROTEIN; CD123 ANTIGEN; CD33 ANTIGEN; CGP 049090; CYCLIN D1; CYTARABINE; DEATH RECEPTOR 4; DEATH RECEPTOR 5; GEMTUZUMAB OZOGAMICIN; HERMES ANTIGEN; HISTONE DEACETYLASE INHIBITOR; IMATINIB; INDIUM 111; MONOCLONAL ANTIBODY; N [1,4,8,11 TETRAAZACYCLOTETRADECANYL 1,4 PHENYLENEBIS(METHYLENE)] 2 (AMINOMETHYL)PYRIDINE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PKF 115584; PLERIXAFOR; RAC1 PROTEIN; RAC2 PROTEIN; STROMAL CELL DERIVED FACTOR 1; UNCLASSIFIED DRUG; UNINDEXED DRUG; VALPROIC ACID; VERY LATE ACTIVATION ANTIGEN 4; WNT PROTEIN;

ACUTE GRANULOCYTIC LEUKEMIA; ANTIGEN EXPRESSION; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; CANCER IMMUNOTHERAPY; CANCER RESEARCH; CANCER STEM CELL; CHRONIC MYELOID LEUKEMIA; COMPLEMENT DEPENDENT CYTOTOXICITY; DRUG DELIVERY SYSTEM; DRUG TARGETING; EPIGENETICS; HUMAN; IMMUNOMODULATION; ISOTOPE LABELING; LEUKEMIA CELL; LIGAND BINDING; NONHUMAN; REVIEW; DRUG EFFECT; GENE EXPRESSION REGULATION; IMMUNOLOGY; LEUKEMIA; PATHOLOGY; SIGNAL TRANSDUCTION; STEM CELL NICHE;

GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; LEUKEMIA; NEOPLASTIC STEM CELLS; SIGNAL TRANSDUCTION; STEM CELL NICHE;

EID: 77949453508     PISSN: 13894501     EISSN: None     Source Type: Journal    
DOI: 10.2174/138945010790031063     Document Type: Review

References (152)

1. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med 2006; 355: 1253-61.
2. Krause DS, Van Etten RA. Right on target: eradicating leukemic stem cells. Trends Mol Med 2007; 13: 470-81.
3. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3: 730-7.
4. 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: 645-8.
5. Castor A, Nilsson L, Astrand-Grundstrom I, Buitenhuis M, Ramirez C, Anderson K, et al. Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia. Nat Med 2005; 11: 630-7.
6. Misaghian N, Ligresti G, Steelman LS, Bertrand FE, Basecke J, Libra M, et al. Targeting the leukemic stem cell: the Holy Grail of leukemia therapy. Leukemia 2009; 23: 25-42.
7. Dalerba P, Cho RW, Clarke MF. Cancer stem cells: models and concepts. Annu Rev Med 2007; 58: 267-84.
8. Hope KJ, Jin L, Dick JE. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol 2004; 5: 738-43.
9. Terpstra W, Ploemacher RE, Prins A, van Lom K, Pouwels K, Wognum AW, et al. Fluorouracil selectively spares acute myeloid leukemia cells with long-term growth abilities in immunodeficient mice and in culture. Blood 1996; 88: 1944-50.
10. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer 2005; 5: 275-84.
11. Lane SW, Scadden DT, Gilliland DG. The leukemic stem cell niche - current concepts and therapeutic opportunities. Blood 2009 [Epub ahead of print].
12. Stel AJ, Ten Cate B, Jacobs S, Kok JW, Spierings DC, Dondorff M, et al. Fas receptor clustering and involvement of the death receptor pathway in rituximab-mediated apoptosis with concomitant sensitization of lymphoma B cells to fas-induced apoptosis. J Immunol 2007; 178: 2287-95.
13. Byrd JC, Kitada S, Flinn IW, Aron JL, Pearson M, Lucas D, et al. The mechanism of tumor cell clearance by rituximab in vivo in patients with B-cell chronic lymphocytic leukemia: evidence of caspase activation and apoptosis induction. Blood 2002; 99: 1038-43.
14. Sato T, Laver JH, Ogawa M. Reversible expression of CD34 by murine hematopoietic stem cells. Blood 1999; 94: 2548-54.
15. Freeman SD, Kelm S, Barber EK, Crocker PR. Characterization of CD33 as a new member of the sialoadhesin family of cellular interaction molecules. Blood 1995; 85: 2005-12.
16. Wellhausen SR, Peiper SC. CD33: biochemical and biological characterization and evaluation of clinical relevance. J Biol Regul Homeost Agents 2002; 16: 139-43.
17. Tchilian EZ, Beverley PC, Young BD, Watt SM. Molecular cloning of two isoforms of the murine homolog of the myeloid CD33 antigen. Blood 1994; 83: 3188-98.
18. Florian S, Sonneck K, Hauswirth AW, Krauth MT, Schernthaner GH, Sperr WR, et al. Detection of molecular targets on the surface of CD34+/CD38 - stem cells in various myeloid malignancies. Leuk Lymphoma 2006; 47: 207-22.
19. Hauswirth AW, Florian S, Printz D, Sotlar K, Krauth MT, Fritsch G, et al. Expression of the target receptor CD33 in CD34+/CD38-/CD123+ AML stem cells. Eur J Clin Invest 2007; 37: 73-82.
20. Jordan CT, Upchurch D, Szilvassy SJ, Guzman ML, Howard DS, Pettigrew AL, et al. The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia 2000; 14: 1777-84.
21. Moretti S, Lanza F, Dabusti M, Tieghi A, Campioni D, Dominici M, et al. CD123 (interleukin 3 receptor alpha chain). J Biol Regul Homeost Agents 2001; 15: 98-100.
22. Marshall AS, Willment JA, Lin HH, Williams DL, Gordon S, Brown GD. Identification and characterization of a novel human myeloid inhibitory C-type lectin-like receptor (MICL) that is predominantly expressed on granulocytes and monocytes. J Biol Chem 2004; 279: 14792-802.
23. Bakker AB, van den Oudenrijn S, Bakker AQ, Feller N, van Meijer M, Bia JA, et al. C-type lectin-like molecule-1: a novel myeloid cell surface marker associated with acute myeloid leukemia. Cancer Res 2004; 64: 8443-50.
24. van Rhenen A, van Dongen GA, Kelder A, Rombouts EJ, Feller N, Moshaver B, et al. The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells. Blood 2007; 110: 2659-66.
25. Moshaver B, van Rhenen A, Kelder A, van der Pol M, Terwijn M, Bachas C, et al. Identification of a small subpopulation of candidate leukemia-initiating cells in the side population of patients with acute myeloid leukemia. Stem Cells 2008; 26: 3059-67.
26. Fuchs A, Cella M, Giurisato E, Shaw AS, Colonna M. Cutting edge: CD96 (tactile) promotes NK cell-target cell adhesion by interacting with the poliovirus receptor (CD155). J Immunol 2004; 172: 3994-8.
27. Gramatzki M, Ludwig WD, Burger R, Moos P, Rohwer P, Grunert C, et al. Antibodies TC-12 ("unique") and TH-111 (CD96) characterize T-cell acute lymphoblastic leukemia and a subgroup of acute myeloid leukemia. Exp Hematol 1998; 26: 1209-14.
28. Hosen N, Park CY, Tatsumi N, Oji Y, Sugiyama H, Gramatzki M, et al. CD96 is a leukemic stem cell-specific marker in human acute myeloid leukemia. Proc Natl Acad Sci U S A 2007; 104: 11008-13.
29. Sun Q, Woodcock JM, Rapoport A, Stomski FC, Korpelainen EI, Bagley CJ, et al. Monoclonal antibody 7G3 recognizes the Nterminal domain of the human interleukin-3 (IL-3) receptor alphachain and functions as a specific IL-3 receptor antagonist. Blood 1996; 87: 83-92.
30. Ten Cate B, Bremer E, de Bruyn M, Bijma T, Samplonius D, Schwemmlein M, et al. A novel AML-selective TRAIL fusion protein that is superior to Gemtuzumab Ozogamicin in terms of in vitro selectivity, activity and stability. Leukemia 2009 Mar 5.
31. Schwemmlein M, Peipp M, Barbin K, Saul D, Stockmeyer B, Repp R, et al. A CD33-specific single-chain immunotoxin mediates potent apoptosis of cultured human myeloid leukaemia cells. Br J Haematol 2006; 133: 141-51.
32. van Der Velden VH, te Marvelde JG, Hoogeveen PG, Bernstein ID, Houtsmuller AB, Berger MS, et al. Targeting of the CD33-calicheamicin immunoconjugate Mylotarg (CMA-676) in acute myeloid leukemia: in vivo and in vitro saturation and internalization by leukemic and normal myeloid cells. Blood 2001; 97: 3197-204.
33. Bross PF, Beitz J, Chen G, Chen XH, Duffy E, Kieffer L, et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res 2001; 7: 1490-6.
34. Larson RA, Sievers EL, Stadtmauer EA, Lowenberg B, Estey EH, Dombret H, et al. Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence. Cancer 2005; 104: 1442-52.
35. Ten Cate B, Samplonius DF, Bijma T, de Leij LF, Helfrich W, Bremer E. The histone deacetylase inhibitor valproic acid potently augments gemtuzumab ozogamicin-induced apoptosis in acute myeloid leukemic cells. Leukemia 2007; 21: 248-52.
36. Walter RB, Gooley TA, van Der Velden VH, Loken MR, van Dongen JJ, Flowers DA, et al. CD33 expression and P-glycoprotein-mediated drug efflux inversely correlate and predict clinical outcome in patients with acute myeloid leukemia treated with gemtuzumab ozogamicin monotherapy. Blood 2007; 109: 4168-70.
37. Kersemans V, Cornelissen B, Minden MD, Brandwein J, Reilly RM. Drug-resistant AML cells and primary AML specimens are killed by 111In-anti-CD33 monoclonal antibodies modified with nuclear localizing peptide sequences. J Nucl Med 2008; 49: 1546-54.
38. Du X, Ho M, Pastan I. New immunotoxins targeting CD123, a stem cell antigen on acute myeloid leukemia cells. J Immunother 2007; 30: 607-13.
39. Testa U, Riccioni R, Biffoni M, Diverio D, Lo-Coco F, Foa R, et al. Diphtheria toxin fused to variant human interleukin-3 induces cytotoxicity of blasts from patients with acute myeloid leukemia according to the level of interleukin-3 receptor expression. Blood 2005; 106: 2527-9.
40. Feuring-Buske M, Frankel AE, Alexander RL, Gerhard B, Hogge DE. A diphtheria toxin-interleukin 3 fusion protein is cytotoxic to primitive acute myeloid leukemia progenitors but spares normal progenitors. Cancer Res 2002; 62: 1730-6.
41. Yalcintepe L, Frankel AE, Hogge DE. Expression of interleukin-3 receptor subunits on defined subpopulations of acute myeloid leukemia blasts predicts the cytotoxicity of diphtheria toxin interleukin-3 fusion protein against malignant progenitors that engraft in immunodeficient mice. Blood 2006; 108: 3530-7.
42. Horita H, Frankel AE, Thorburn A. Acute-myeloid-leukemiatargeted toxins kill tumor cells by cell-type-specific mechanisms and synergize with TRAIL to allow manipulation of the extent and mechanism of tumor cell death. Leukemia 2008; 22: 652-5.
43. Ashkenazi A. Targeting the extrinsic apoptosis pathway in cancer. Cytokine Growth Factor Rev 2008; 19: 325-31.
44. Tolcher AW, Mita M, Meropol NJ, von Mehren M, Patnaik A, Padavic K, et al. Phase I pharmacokinetic and biologic correlative study of mapatumumab, a fully human monoclonal antibody with agonist activity to tumor necrosis factor-related apoptosis-inducing ligand receptor-1. J Clin Oncol 2007; 25: 1390-5.
45. Hotte SJ, Hirte HW, Chen EX, Siu LL, Le LH, Corey A, et al. A phase 1 study of mapatumumab (fully human monoclonal antibody to TRAIL-R1) in patients with advanced solid malignancies. Clin Cancer Res 2008; 14: 3450-5.
46. Plummer R, Attard G, Pacey S, Li L, Razak A, Perrett R, et al. Phase 1 and pharmacokinetic study of lexatumumab in patients with advanced cancers. Clin Cancer Res 2007; 13: 6187-94.
47. Ashkenazi A. Directing cancer cells to self-destruct with proapoptotic receptor agonists. Nat Rev Drug Discov 2008; 7: 1001-12.
48. Bremer E, de Bruyn M, Wajant H, Helfrich W. Targeted cancer immunotherapy using ligands of the tumor necrosis factor superfamily. Curr Drug Targets 2009; 10: 94-103.
49. Bremer E, van Dam GM, de Bruyn M, van Riezen M, Dijkstra M, Kamps G, et al. Potent systemic anticancer activity of adenovirally expressed EGFR-selective TRAIL fusion protein. Mol Ther 2008; 16: 1919-26.
50. Bremer E, Samplonius DF, van Genne L, Dijkstra MH, Kroesen BJ, de Leij LF, et al. Simultaneous inhibition of epidermal growth factor receptor (EGFR) signaling and enhanced activation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-mediated apoptosis induction by an scFv:sTRAIL fusion protein with specificity for human EGFR. J Biol Chem 2005; 280: 10025-33.
51. Bremer E, de Bruyn M, Samplonius DF, Bijma T, Ten Cate B, de Leij LF, et al. Targeted delivery of a designed sTRAIL mutant results in superior apoptotic activity towards EGFR-positive tumor cells. J Mol Med 2008; 86: 909-24.
52. Bremer E, Samplonius D, Kroesen BJ, van Genne L, de Leij L, Helfrich W. Exceptionally potent anti-tumor bystander activity of an scFv:sTRAIL fusion protein with specificity for EGP2 toward target antigen-negative tumor cells. Neoplasia 2004; 6: 636-45.
53. Bremer E, Kuijlen J, Samplonius D, Walczak H, de Leij L, Helfrich W. Target cell-restricted and -enhanced apoptosis induction by a scFv:sTRAIL fusion protein with specificity for the pancarcinoma-associated antigen EGP2. Int J Cancer 2004; 109: 281-90.
54. Bremer E, Samplonius DF, Peipp M, van Genne L, Kroesen BJ, Fey GH, et al. Target cell-restricted apoptosis induction of acute leukemic T cells by a recombinant tumor necrosis factor-related apoptosis-inducing ligand fusion protein with specificity for human CD7. Cancer Res 2005; 65: 3380-8.
55. Stieglmaier J, Bremer E, Kellner C, Liebig TM, Ten Cate B, Peipp M, et al. Selective induction of apoptosis in leukemic B-lymphoid cells by a CD19-specific TRAIL fusion protein. Cancer Immunol Immunother 2008; 57: 233-46.
56. Majeti R, Becker MW, Tian Q, Lee TL, Yan X, Liu R, et al. Dysregulated gene expression networks in human acute myelogenous leukemia stem cells. Proc Natl Acad Sci USA 2009 [Epub ahead of print].
57. Yong A, Keyvanfar K, Hensel N, Eniafe R, Savani B, Berg M, et al. Primitive quiescent CD34+ cells in chronic myeloid leukemia are targeted by in vitro expanded natural killer cells, which are functionally enhanced by bortezomib. Blood 2009; 113: 875-82.
58. Tazzari PL, Tabellini G, Ricci F, Papa V, Bortul R, Chiarini F, et al. Synergistic proapoptotic activity of recombinant TRAIL plus the Akt inhibitor Perifosine in acute myelogenous leukemia cells. Cancer Res 2008; 68: 9394-403.
59. Schofield R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 1978; 4: 7-25.
60. Nilsson SK, Johnston HM, Coverdale JA. Spatial localization of transplanted hemopoietic stem cells: inferences for the localization of stem cell niches. Blood 2001; 97: 2293-9.
61. Kiel MJ, Morrison SJ. Uncertainty in the niches that maintain haematopoietic stem cells. Nat Rev Immunol 2008; 8: 290-301.
62. Colmone A, Amorim M, Pontier AL, Wang S, Jablonski E, Sipkins DA. Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progenitor cells. Science 2008; 322: 1861-5.
63. Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S, et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol 2007; 25: 1315-21.
64. Peled A, Petit I, Kollet O, Magid M, Ponomaryov T, Byk T, et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 1999; 283: 845-8.
65. Sugiyama T, Kohara H, Noda M, Nagasawa T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 2006; 25: 977-88.
66. Tavor S, Petit I, Porozov S, Avigdor A, Dar A, Leider-Trejo L, et al. CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice. Cancer Res 2004; 64: 2817-24.
67. Spoo AC, Lubbert M, Wierda WG, Burger JA. CXCR4 is a prognostic marker in acute myelogenous leukemia. Blood 2007; 109: 786-91.
68. Rombouts EJ, Pavic B, Lowenberg B, Ploemacher RE. Relation between CXCR-4 expression, Flt3 mutations, and unfavorable prognosis of adult acute myeloid leukemia. Blood 2004; 104: 550-7.
69. Broxmeyer HE, Orschell CM, Clapp DW, Hangoc G, Cooper S, Plett PA, et al. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med 2005; 201: 1307-18.
70. Nervi B, Ramirez P, Rettig MP, Uy GL, Holt MS, Ritchey JK, et al. Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100. Blood 2009; 113: 6206-14.
71. Zeng Z, Shi YX, Samudio IJ, Wang RY, Ling X, Frolova O, et al. Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML. Blood 2009; 113: 6215-24.
72. Burger JA, Peled A. CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers. Leukemia 2009; 23: 43-52.
73. Li H, Guo L, Jie S, Liu W, Zhu J, Du W, et al. Berberine inhibits SDF-1-induced AML cells and leukemic stem cells migration via regulation of SDF-1 level in bone marrow stromal cells. Biomed Pharmacother 2008; 62: 573-8.
74. Papayannopoulou T, Priestley GV, Nakamoto B, Zafiropoulos V, Scott LM. Molecular pathways in bone marrow homing: dominant role of alpha(4)beta(1) over beta(2)-integrins and selectins. Blood 2001; 98: 2403-11.
75. Matsunaga T, Takemoto N, Sato T, Takimoto R, Tanaka I, Fujimi A, et al. Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. Nat Med 2003; 9: 1158-65.
76. Kato R, Ishikawa T, Kamiya S, Oguma F, Ueki M, Goto S, et al. A new type of antimetastatic peptide derived from fibronectin. Clin Cancer Res 2002; 8: 2455-62.
77. Matsunaga T, Fukai F, Miura S, Nakane Y, Owaki T, Kodama H, et al. Combination therapy of an anticancer drug with the FNIII14 peptide of fibronectin effectively overcomes cell adhesionmediated drug resistance of acute myelogenous leukemia. Leukemia 2008; 22: 353-60.
78. Avigdor A, Goichberg P, Shivtiel S, Dar A, Peled A, Samira S, et al. CD44 and hyaluronic acid cooperate with SDF-1 in the trafficking of human CD34+ stem/progenitor cells to bone marrow. Blood 2004; 103: 2981-9.
79. Sackstein R, Merzaban JS, Cain DW, Dagia NM, Spencer JA, Lin CP, et al. Ex vivo glycan engineering of CD44 programs human multipotent mesenchymal stromal cell trafficking to bone. Nat Med 2008; 14: 181-7.
80. Krause DS, Lazarides K, von Andrian UH, Van Etten RA. Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells. Nat Med 2006; 12: 1175-80.
81. Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 2006; 12: 1167-74.
82. 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: 319-25.
83. Moll J, Sansig G, Fattori E, van der Putten H. The murine rac1 gene: cDNA cloning, tissue distribution and regulated expression of rac1 mRNA by disassembly of actin microfilaments. Oncogene 1991; 6: 863-6.
84. Shirsat NV, Pignolo RJ, Kreider BL, Rovera G. A member of the ras gene superfamily is expressed specifically in T, B and myeloid hemopoietic cells. Oncogene 1990; 5: 769-72.
85. Haataja L, Groffen J, Heisterkamp N. Characterization of RAC3, a novel member of the Rho family. J Biol Chem 1997; 272: 20384-8.
86. Gu Y, Filippi MD, Cancelas JA, Siefring JE, Williams EP, Jasti AC, et al. Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatases. Science 2003; 302: 445-9.
87. Gao Y, Dickerson JB, Guo F, Zheng J, Zheng Y. Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc Natl Acad Sci U S A 2004; 101: 7618-23.
88. Muller LU, Schore RJ, Zheng Y, Thomas EK, Kim MO, Cancelas JA, et al. Rac guanosine triphosphatases represent a potential target in AML. Leukemia 2008; 22: 1803-6.
89. Rozenveld-Geugien M, Baas IO, van Gosliga D, Vellenga E, Schuringa JJ. Expansion of normal and leukemic human hematopoietic stem/progenitor cells requires rac-mediated interaction with stromal cells. Exp Hematol 2007; 35: 782-92.
90. Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis. Nature 2004; 432: 324-31.
91. Rohatgi R, Scott MP. Patching the gaps in Hedgehog signalling. Nat Cell Biol 2007; 9: 1005-9.
92. Duman-Scheel M, Weng L, Xin S, Du W. Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E. Nature 2002; 417: 299-304.
93. Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res 2006; 66: 6063-71.
94. Chen JK, Taipale J, Cooper MK, Beachy PA. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev 2002; 16: 2743-8.
95. 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: 776-9.
96. 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: 409-14.
97. Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature 2005; 434: 843-50.
98. Giles RH, van Es JH, Clevers H. Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta 2003; 1653: 1-24.
99. He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, et al. Identification of c-MYC as a target of the APC pathway. Science 1998; 281: 1509-12.
100. Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 1999; 398: 422-6.
101. Wielenga VJ, Smits R, Korinek V, Smit L, Kielman M, Fodde R, et al. Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway. Am J Pathol 1999; 154: 515-23.
102. Muller-Tidow C, Steffen B, Cauvet T, Tickenbrock L, Ji P, Diederichs S, et al. Translocation products in acute myeloid leukemia activate the Wnt signaling pathway in hematopoietic cells. Mol Cell Biol 2004; 24: 2890-904.
103. Mikesch JH, Steffen B, Berdel WE, Serve H, Muller-Tidow C. The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia. Leukemia 2007; 21: 1638-47.
104. 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: 528-41.
105. 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: 109-16.
106. Kawano Y, Kypta R. Secreted antagonists of the Wnt signalling pathway. J Cell Sci 2003; 116: 2627-34.
107. Zhu Y, Sun Z, Han Q, Liao L, Wang J, Bian C, et al. Human mesenchymal stem cells inhibit cancer cell proliferation by secreting DKK-1. Leukemia 2009; 23: 925-33.
108. Lepourcelet M, Chen YN, France DS, Wang H, Crews P, Petersen F, et al. Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell 2004; 5: 91-102.
109. Minke KS, Staib P, Puetter A, Gehrke I, Gandhirajan RK, Schlosser A, et al. Small molecule inhibitors of WNT signaling effectively induce apoptosis in acute myeloid leukemia cells. Eur J Haematol 2009; 82: 165-75.
110. Sophos NA, Vasiliou V. Aldehyde dehydrogenase gene superfamily: the 2002 update. Chem Biol Interact 2003; 143-144: 5-22.
111. Moreb JS, Mohuczy D, Ostmark B, Zucali JR. RNAi-mediated knockdown of aldehyde dehydrogenase class-1A1 and class-3A1 is specific and reveals that each contributes equally to the resistance against 4-hydroperoxycyclophosphamide. Cancer Chemother Pharmacol 2007; 59: 127-36.
112. Pearce DJ, Taussig D, Simpson C, Allen K, Rohatiner AZ, Lister TA, et al. Characterization of cells with a high aldehyde dehydrogenase activity from cord blood and acute myeloid leukemia samples. Stem Cells 2005; 23: 752-60.
113. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 2007; 1: 555-67.
114. Ma S, Chan KW, Lee TK, Tang KH, Wo JY, Zheng BJ, et al. Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations. Mol Cancer Res 2008; 6: 1146-53.
115. Cheung AM, Wan TS, Leung JC, Chan LY, Huang H, Kwong YL, et al. Aldehyde dehydrogenase activity in leukemic blasts defines a subgroup of acute myeloid leukemia with adverse prognosis and superior NOD/SCID engrafting potential. Leukemia 2007; 21: 1423-30.
116. Dylla SJ, Beviglia L, Park IK, Chartier C, Raval J, Ngan L, et al. Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy. PLoS ONE 2008; 3: e2428.
117. Ryningen A, Stapnes C, Paulsen K, Lassalle P, Gjertsen BT, Bruserud O. In vivo biological effects of ATRA in the treatment of AML. Expert Opin Investig Drugs 2008; 17: 1623-33.
118. Dahia PL, Aguiar RC, Alberta J, Kum JB, Caron S, Sill H, et al. PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanismsin haematological malignancies. Hum Mol Genet 1999; 8: 185-93.
119. Cheong JW, Eom JI, Maeng HY, Lee ST, Hahn JS, Ko YW, et al. Phosphatase and tensin homologue phosphorylation in the Cterminal regulatory domain is frequently observed in acute myeloid leukaemia and associated with poor clinical outcome. Br J Haematol 2003; 122: 454-6.
120. Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 1998; 273: 13375-8.
121. Yilmaz OH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 2006; 441: 475-82.
122. Ito K, Bernardi R, Morotti A, Matsuoka S, Saglio G, Ikeda Y, et al. PML targeting eradicates quiescent leukaemia-initiating cells. Nature 2008; 453: 1072-8.
123. Martinez A, Alonso M, Castro A, Perez C, Moreno FJ. First non-ATP competitive glycogen synthase kinase 3 beta (GSK-3beta) inhibitors: thiadiazolidinones (TDZD) as potential drugs for the treatment of Alzheimer's disease. J Med Chem 2002; 45: 1292-9.
124. Abrahamsson AE, Geron I, Gotlib J, Dao KH, Barroga CF, Newton IG, et al. Glycogen synthase kinase 3beta missplicing contributes to leukemia stem cell generation. Proc Natl Acad Sci U S A 2009; 106: 3925-9.
125. Guzman ML, Li X, Corbett CA, Rossi RM, Bushnell T, Liesveld JL, et al. Rapid and selective death of leukemia stem and progenitor cells induced by the compound 4-benzyl, 2-methyl, 1,2,4-thiadiazolidine, 3,5 dione (TDZD-8). Blood 2007; 110: 4436-44.
126. Steele AJ, Jones DT, Ganeshaguru K, Duke VM, Yogashangary BC, North JM, et al. The sesquiterpene lactone parthenolide induces selective apoptosis of B-chronic lymphocytic leukemia cells in vitro. Leukemia 2006; 20: 1073-9.
127. Wen J, You KR, Lee SY, Song CH, Kim DG. Oxidative stress-mediated apoptosis. The anticancer effect of the sesquiterpene lactone parthenolide. J Biol Chem 2002; 277: 38954-64.
128. Oka D, Nishimura K, Shiba M, Nakai Y, Arai Y, Nakayama M, et al. Sesquiterpene lactone parthenolide suppresses tumor growth in a xenograft model of renal cell carcinoma by inhibiting the activation of NF-kappaB. Int J Cancer 2007; 120: 2576-81.
129. Guzman ML, Rossi RM, Karnischky L, Li X, Peterson DR, Howard DS, et al. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 2005; 105: 4163-9.
130. Guzman ML, Rossi RM, Neelakantan S, Li X, Corbett CA, Hassane DC, et al. An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells. Blood 2007; 110: 4427-35.
131. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57-70.
132. Jones PA, Baylin SB. The epigenomics of cancer. Cell 2007; 128: 683-92.
133. Ringrose L, Paro R. Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu Rev Genet 2004; 38: 413-43.
134. Schuebel K, Chen W, Baylin SB. CIMPle origin for promoter hypermethylation in colorectal cancer? Nat Genet 2006; 38: 738-40.
135. Widschwendter M, Fiegl H, Egle D, Mueller-Holzner E, Spizzo G, Marth C, et al. Epigenetic stem cell signature in cancer. Nat Genet 2007; 39: 157-8.
136. Park IK, Qian D, Kiel M, Becker MW, Pihalja M, Weissman IL, et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 2003; 423: 302-5.
137. Chowdhury M, Mihara K, Yasunaga S, Ohtaki M, Takihara Y, Kimura A. Expression of Polycomb-group (PcG) protein BMI-1 predicts prognosis in patients with acute myeloid leukemia. Leukemia 2007; 21: 1116-22.
138. Mohty M, Yong AS, Szydlo RM, Apperley JF, Melo JV. The polycomb group BMI1 gene is a molecular marker for predicting prognosis of chronic myeloid leukemia. Blood 2007; 110: 380-3.
139. Wang GG, Song J, Wang Z, Dormann HL, Casadio F, Li H, et al. Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger. Nature 2009; 459: 847-51.
140. Taverna SD, Li H, Ruthenburg AJ, Allis CD, Patel DJ. How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat Struct Mol Biol 2007; 14: 1025-40.
141. Baker LA, Allis CD, Wang GG. PHD fingers in human diseases: disorders arising from misinterpreting epigenetic marks. Mutat Res 2008; 647: 3-12.
142. van Zutven LJ, Onen E, Velthuizen SC, van Drunen E, von Bergh AR, van den Heuvel-Eibrink MM et al. Identification of NUP98 abnormalities in acute leukemia: JARID1A (12p13) as a new partner gene. Genes Chromosomes Cancer 2006; 45: 437-46.
143. Wang GG, Cai L, Pasillas MP, Kamps MP. NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nat Cell Biol 2007; 9: 804-12.
144. Moore MA, Chung KY, Plasilova M, Schuringa JJ, Shieh JH, Zhou P, et al. NUP98 dysregulation in myeloid leukemogenesis. Ann N Y Acad Sci 2007; 1106: 114-42.
145. Wang GG, Song J, Wang Z, Dormann HL, Casadio F, Li H, et al. Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger. Nature 2009.
146. Lessard J, Sauvageau G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 2003; 423: 255-60.
147. Liang G, Gonzales FA, Jones PA, Orntoft TF, Thykjaer T. Analysis of gene induction in human fibroblasts and bladder cancer cells exposed to the methylation inhibitor 5-aza-2'-deoxycytidine. Cancer Res 2002; 62: 961-6.
148. Kuendgen A, Gattermann N. Valproic acid for the treatment of myeloid malignancies. Cancer 2007; 110: 943-54.
149. Guo F, Sigua C, Tao J, Bali P, George P, Li Y, et al. Cotreatment with histone deacetylase inhibitor LAQ824 enhances Apo-2L/tumor necrosis factor-related apoptosis inducing ligand-induced death inducing signaling complex activity and apoptosis of human acute leukemia cells. Cancer Res 2004; 64: 2580-9.
150. Morotti A, Cilloni D, Messa F, Arruga F, Defilippi I, Carturan S, et al. Valproate enhances imatinib-induced growth arrest and apoptosis in chronic myeloid leukemia cells. Cancer 2006; 106: 1188-96.
151. Yu C, Rahmani M, Conrad D, Subler M, Dent P, Grant S. The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571. Blood 2003; 102: 3765-74.
152. Saito Y, Liang G, Egger G, Friedman JM, Chuang JC, Coetzee GA, et al. Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell 2006; 9: 435-43.