Dendritic cells in myelodysplastic syndromes: From pathogenesis to immunotherapy

Immunotherapy

Volumn 5, Issue 6, 2013, Pages 621-637

  Kerkhoff, Nathalie ^a   Bontkes, Hetty J ^a   Westers, Theresia M ^a   De Gruijl, Tanja D ^a   Kordasti, Shahram ^b   Van De Loosdrecht, Arjan A ^a  

^a VU UNIVERSITY MEDICAL CENTER   (Netherlands)

^b KING S COLLEGE HOSPITAL   (United Kingdom)

Author keywords

azacitidine; dendritic cell; dendritic cell vaccination; immunotherapy; lenalidomide; myelodysplastic syndrome

Indexed keywords

5 AZA 2' DEOXYCYTIDINE; AZACITIDINE; DENDRITIC CELL VACCINE; GAMMA INTERFERON INDUCIBLE PROTEIN 10; HLA DR ANTIGEN; INTERLEUKIN 17; INTERLEUKIN 6; INTERLEUKIN 8; LENALIDOMIDE; MACROPHAGE INFLAMMATORY PROTEIN 1ALPHA; MACROPHAGE INFLAMMATORY PROTEIN 1BETA; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2; RANTES; TOLL LIKE RECEPTOR; TUMOR NECROSIS FACTOR ALPHA; VALPROIC ACID;

ACUTE GRANULOCYTIC LEUKEMIA; ANTIGEN PRESENTATION; APOPTOSIS; BONE MARROW TRANSPLANTATION; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL CYCLE PROGRESSION; CELL DIFFERENTIATION; COMPETITIVE INHIBITION; CROSS PRESENTATION; CYTOKINE PRODUCTION; CYTOTOXIC T LYMPHOCYTE; DENDRITIC CELL; DNA METHYLATION; EFFECTOR CELL; EPIGENETICS; HISTONE MODIFICATION; HUMAN; IMMUNE RESPONSE; IMMUNOSURVEILLANCE; IMMUNOTHERAPY; LYMPHOCYTE SUBPOPULATION; MINIMAL RESIDUAL DISEASE; MYELODYSPLASTIC SYNDROME; NATURAL KILLER CELL; NONHUMAN; PATHOGENESIS; PHENOTYPE; PLASMACYTOID DENDRITIC CELL; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN TARGETING; RECURRENCE FREE SURVIVAL; REGULATORY T LYMPHOCYTE; REVIEW; SIGNAL TRANSDUCTION; TH17 CELL;

ANIMALS; DENDRITIC CELLS; HEMATOPOIETIC STEM CELLS; HUMANS; IMMUNOTHERAPY; MYELODYSPLASTIC SYNDROMES;

EID: 84878722278     PISSN: 1750743X     EISSN: 17507448     Source Type: Journal    
DOI: 10.2217/imt.13.51     Document Type: Review

References (173)

1. Greenberg PL, Tuechler H, Schanz J et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 120(12), 2454-2465 (2012).
2. Malcovati L, Germing U, Kuendgen A et al. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J. Clin. Oncol. 25(23), 3503-3510 (2007).
3. Malcovati L, Della Porta MG, Strupp C et al. Impact of the degree of anemia on the outcome of patients with myelodysplastic syndrome and its integration into the WHO classification-based Prognostic Scoring System (WPSS). Haematologica 96(10), 1433-1440 (2011).
4. Aggerholm A, Holm MS, Guldberg P, Olesen LH, Hokland P. Promoter hypermethylation of p15INK4B, HIC1, CDH1, and ER is frequent in myelodysplastic syndrome and predicts poor prognosis in early-stage patients. Eur. J. Haematol. 76(1), 23-32 (2006).
5. Nolte F, Hofmann WK. Myelodysplastic syndromes: molecular pathogenesis and genomic changes. Ann. Hematol. 87(10), 777-795 (2008).
6. Bejar R, Levine R, Ebert BL. Unraveling the molecular pathophysiology of myelodysplastic syndromes. J. Clin. Oncol. 29(5), 504-515 (2011).
7. Epperson DE, Nakamura R, Saunthararajah Y, Melenhorst J, Barrett AJ. Oligoclonal T cell expansion in myelodysplastic syndrome: evidence for an autoimmune process. Leuk. Res. 25(12), 1075-1083 (2001).
8. Voulgarelis M, Giannouli S, Ritis K, Tzioufas AG. Myelodysplasia- associated autoimmunity: clinical and pathophysiologic concepts. Eur. J. Clin. Invest. 34(10), 690-700 (2004).
9. Pülhorn H, Herrmann M, Harms H, Jung A, Baumann I. Apoptotic cells and clonally expanded cytotoxic T cells in bone marrow trephines of patients with myelodysplastic syndrome. Histopathology 61(2), 200-211 (2012).
10. Yazji S, Giles FJ, Tsimberidou AM et al. Antithymocyte globulin (ATG)-based therapy in patients with myelodysplastic syndromes. Leukemia 17(11), 2101-2106 (2003).
11. Passweg JR, Giagounidis AA, Simcock M et al. Immunosuppressive therapy for patients with myelodysplastic syndrome: a prospective randomized multicenter Phase III trial comparing antithymocyte globulin plus cyclosporine with best supportive care-SAKK 33/99. J. Clin. Oncol. 29(3), 303-309 (2011).
12. Kordasti SY, Afzali B, Lim Z et al. IL 17-producing CD4+ T cells, pro-inflammatory cytokines and apoptosis are increased in low risk myelodysplastic syndrome. Br. J. Haematol. 145(1), 64-72 (2009).
13. Kordasti SY, Ingram W, Hayden J et al. CD4+CD25high Foxp3+ regulatory T cells in myelodysplastic syndrome (MDS). Blood 110(3), 847-850 (2007).
14. Kotsianidis I, Bouchliou I, Nakou E et al. Kinetics, function and bone marrow trafficking of CD4+CD25+FOXP3+ regulatory T cells in myelodysplastic syndromes (MDS). Leukemia 23(3), 510-518 (2009).
15. Bouchliou I, Miltiades P, Nakou E et al. Th17 and Foxp3+ T regulatory cell dynamics and distribution in myelodysplastic syndromes. Clin. Immunol. 139(3), 350-359 (2011).
16. Kiladjian JJ, Bourgeois E, Lobe I et al. Cytolytic function and survival of natural killer cells are severely altered in myelodysplastic syndromes. Leukemia 20(3), 463-470 (2006).
17. Epling-Burnette PK, Bai F, Painter JS et al. Reduced natural killer (NK) function associated with high-risk myelodysplastic syndrome (MDS) and reduced expression of activating NK receptors. Blood 109(11), 4816-4824 (2007).
18. Chamuleau MED, Westers TM, Van Dreunen L et al. Immune mediated autologous cytotoxicity against hematopoietic precursor cells in patients with myelodysplastic syndrome. Haematologica 94(4), 496-506 (2009).
19. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 392(6673), 245-252 (1998). .
20. Banchereau J, Briere F, Caux C et al. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767-811 (2000).
21. MacDonald KP, Munster DJ, Clark GJ, Dzionek A, Schmitz J, Hart DN. Characterization of human blood dendritic cell subsets. Blood 100(13), 4512-4520 (2002).
22. Ziegler-Heitbrock L, Ancuta P, Crowe S et al. Nomenclature of monocytes and dendritic cells in blood. Blood 116(16), e74-e80 (2010).
23. Harman AN, Bye CR, Nasr N et al. Identification of lineage relationships and novel markers of blood and skin human dendritic cells. J. Immunol. 190(1), 66-79 (2012).
24. Kadowaki N, Ho S, Antonenko S et al. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J. Exp. Med. 194(6), 863-869 (2001).
25. Jarrossay D, Napolitani G, Colonna M, Sallusto F, Lanzavecchia A. Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells. Eur. J. Immunol. 31(11), 3388-3393 (2001).
26. Bao M, Liu YJ. Regulation of TLR7/9 signaling in plasmacytoid dendritic cells. Protein Cell 4(1), 40-52 (2013).
27. Siegal FP. The nature of the principal type 1 interferon-producing cells in human blood. Science 284(5421), 1835-1837 (1999).
28. Cella M, Jarrossay D, Facchetti F et al. Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nature Med. 5(8), 919-923 (1999).
29. Dzionek A, Fuchs A, Schmidt P et al. BDCA 2, BDCA 3, and BDCA 4: three markers for distinct subsets of dendritic cells in human peripheral blood. J. Immunol. 165(11), 6037-6046 (2000).
30. Dzionek A, Sohma Y, Nagafune J et al. BDCA 2, a novel plasmacytoid dendritic cell-specific type II C-type lectin, mediates antigen capture and is a potent inhibitor of interferon alpha/beta induction. J. Exp. Med. 194(12), 1823-1834 (2001).
31. Hémont C, Neel A, Heslan M, Braudeau C, Josien R. Human blood mDC subsets exhibit distinct TLR repertoire and responsiveness. J. Leuk. Biol. 93, 1-11 (2013).
32. ν Demonstrates Toll-like receptor expression on different dendritic cell subsets indicating functional differences between the subsets.
33. Schulz O, Diebold S, Chen M et al. Toll-like receptor 3 promotes cross-priming to virus-infected cells. Nature 433, 887-892 (2005).
34. Le Bon A, Tough DF. Type I interferon as a stimulus for cross-priming. Cytokine Growth Factor Rev. 19(1), 33-40 (2008).
35. Jongbloed SL, Kassianos AJ, McDonald KJ et al. Human CD141+ (BDCA 3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J. Exp. Med. 207(6), 1247-1260 (2010).
36. Orabona C, Puccetti P, Vacca C et al. Toward the identification of a tolerogenic signature in IDO-competent dendritic cells. Blood 107(7), 2846-2854 (2006).
37. Curti A, Trabanelli S, Onofri C et al. Indoleamine 2,3-dioxygenase- expressing leukemic dendritic cells impair a leukemia-specific immune response by inducing potent T regulatory cells. Haematologica 95(12), 2022-2030 (2010).
38. Chamuleau ME, Van de Loosdrecht AA, Hess CJ et al. High INDO (indoleamine 2,3-dioxygenase) mRNA level in blasts of acute myeloid leukemic patients predicts poor clinical outcome. Haematologica 93(12), 1894-1898 (2008).
39. Schakel K, Mayer E, Federle C, Schmitz M, Riethmüller G, Rieber EP. A novel dendritic cell population in human blood: one-step immunomagnetic isolation by a specific mAb (M-DC8) and in vitro priming of cytotoxic T lymphocytes. Eur. J. Immunol. 28(12), 4084-4093 (1998).
40. Schakel K, Von Kietzell M, Hansel A et al. Human 6-sulfo LacNAc-expressing dendritic cells are principal producers of early interleukin-12 and are controlled by erythrocytes. Immunity 24(6), 767-777 (2006).
41. Schakel K, Kannagi R, Kniep B et al. 6-sulfo LacNAc, a novel carbohydrate modification of PSGL-1, defines an inflammatory type of human dendritic cells. Immunity 17(3), 289-301 (2002).
42. Schmitz M, Zhao S, Deuse Y et al. Tumoricidal potential of native blood dendritic cells: direct tumor cell killing and activation of NK cell-mediated cytotoxicity. J. Immunol. 174(7), 4127-4134 (2005).
43. Bippes CC, Feldmann A, Stamova S et al. A novel modular antigen delivery system for immuno targeting of human 6-sulfo LacNAc-positive blood dendritic cells (slanDCs). PLoS ONE 6(1), e16315 (2011).
44. Zhu J, Paul WE. CD4 T cells: fates, functions, and faults. Blood 112(5), 1557-1569 (2008).
45. Strainic MG, Shevach EM, An F, Lin F, Medof ME. Absence of signaling into CD4+ cells via C3aR and C5aR enables autoinductive TGF-b1 signaling and induction of Foxp3+ regulatory T cells. Nat. Immunol. 14(2), 162-171 (2012).
46. Kapsenberg ML. Dendritic-cell control of pathogen-driven T-cell polarization. Nat. Rev. Immunol. 3(12), 984-993 (2003).
47. Kadowaki N, Antonenko S, Lau JY, Liu YJ. Natural interferon alpha/beta-producing cells link innate and adaptive immunity. J. Exp. Med. 192(2), 219-226 (2000).
48. Smits HH, De Jong EC, Schuitemaker JH et al. Intercellular adhesion molecule-1/LFA-1 ligation favors human Th1 development. J. Immunol. 168(4), 1710-1716 (2002).
49. Lichtenegger FS, Mueller K, Otte B et al. CD86 and IL 12p70 are key players for T helper 1 polarization and natural killer cell activation by Toll-like receptor-induced dendritic cells. PLoS ONE 7(9), e44266 (2012).
50. Athie-Morales V, Smits HH, Cantrell DA, Hilkens CM. Sustained IL 12 signaling is required for Th1 development. J. Immunol. 172(1), 61-69 (2004).
51. Paul WE, Zhu J. How are T(H)2-type immune responses initiated and amplified? Nature Rev. Immunol. 10(4), 225-235 (2010).
52. Kim M, Bekiaris V, Mcconnell FM et al. OX40 signals during priming on dendritic cells inhibit CD4 T cell proliferation: IL 4 switches off OX40 signals enabling rapid proliferation of Th2 effectors. J. Immunol. 174(3), 1433-1437 (2005).
53. Swain SL, Weinberg a D, English M, Huston G. IL 4 directs the development of Th2-like helper effectors. J. Immunol. 145(11), 3796-3806 (1990).
54. Zhou L, Ivanov II, Spolski R et al. IL 6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL 21 and IL 23 pathways. Nat. Immunol. 8(9), 967-974 (2007).
55. Volpe E, Servant N, Zollinger R et al. A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat. Immunol. 9(6), 650-657 (2008).
56. Yang L, Anderson DE, Baecher-Allan C et al. IL 21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature 454(7202), 350-352 (2008).
57. Zeller JC, Panoskaltsis-Mortari A, Murphy WJ et al. Induction of CD4+ T cell alloantigen-specific hyporesponsiveness by IL 10 and TGF-beta. J. Immunol. 163(7), 3684-3691 (1999).
58. Boks MA, Kager-Groenland JR, Haasjes MS, Zwaginga JJ, Van Ham SM, Ten Brinke A. IL 10-generated tolerogenic dendritic cells are optimal for functional regulatory T cell induction-a comparative study of human clinical-applicable DC. Clin. Immunol. 142(3), 332-342 (2012).
59. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100(6), 655-669 (2000).
60. Kaplan MH, Schindler U, Smiley ST, Grusby MJ. Stat6 is required for mediating responses to IL 4 and for development of Th2 cells. Immunity 4(3), 313-319 (1996).
61. Ouyang W, Ranganath SH, Weindel K et al. Inhibition of Th1 development mediated by GATA-3 through an IL 4-independent mechanism. Immunity 9(5), 745-755 (1998).
62. Zhu J, Min B, Hu-Li J et al. Conditional deletion of Gata3 shows its essential function in T(H)1-T(H)2 responses. Nat. Immunol. 5(11), 1157-1165 (2004).
63. Zhu J, Cote-Sierra J, Guo L, Paul WE. Stat5 activation plays a critical role in Th2 differentiation. Immunity 19(5), 739-748 (2003).
64. Lin JX, Leonard WJ. The role of Stat5a and Stat5b in signaling by IL 2 family cytokines. Oncogene 19(21), 2566-2576 (2000).
65. Manel N, Unutmaz D, Littman DR. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat. Immunol. 9(6), 641-649 (2008).
66. Harris TJ, Grosso JF, Yen H et al. Cutting edge: an in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity. J. Immunol. 179, 4313-4317 (2007).
67. Chen W, Jin W, Hardegen N et al. Conversion of peripheral CD4+CD25-naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J. Exp. Med. 198(12), 1875-1886 (2003).
68. O'Shea JJ, Paul WE. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327(5969), 1098-1102 (2010).
69. Joffre OP, Segura E, Savina A, Amigorena S. Cross-presentation by dendritic cells. Nature Rev. Immunol. 12, 557-569 (2012).
70. Kurts C, Robinson BW, Knolle PA. Cross-priming in health and disease. Nat. Rev. Immunol. 10(6), 403-414 (2010).
71. Den Haan JM, Lehar SM, Bevan MJ. CD8+ but not CD8-dendritic cells cross-prime cytotoxic T cells in vivo. J. Exp. Med. 192(12), 1685-1696 (2000).
72. Robbins SH, Walzer T, Dembélé D et al. Novel insights into the relationships between dendritic cell subsets in human and mouse revealed by genome-wide expression profiling. Genome Biol. 9(1), R17 (2008).
73. Crozat K, Guiton R, Guilliams M et al. Comparative genomics as a tool to reveal functional equivalences between human and mouse dendritic cell subsets. Immunol. Rev. 234(1), 177-198 (2010).
74. Bachem A, Güttler S, Hartung E et al. Superior antigen cross-presentation and XCR1 expression define human CD11c+CD141+ cells as homologues of mouse CD8+ dendritic cells. J. Exp. Med. 207(6), 1273-1281 (2010).
75. Crozat K, Guiton R, Contreras V et al. The XC chemokine receptor 1 is a conserved selective marker of mammalian cells homologous to mouse CD8alpha+ dendritic cells. J. Exp. Med. 207(6), 1283-1292 (2010).
76. Dorner BG, Dorner MB, Zhou X et al. Selective expression of the chemokine receptor XCR1 on cross-presenting dendritic cells determines cooperation with CD8+ T cells. Immunity 31(5), 823-833 (2009).
77. Zhang JG, Czabotar PE, Policheni AN et al. The dendritic cell receptor Clec9A binds damaged cells via exposed actin filaments. Immunity 36(4), 646-657 (2012).
78. Poulin LF, Salio M, Griessinger E et al. Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8alpha+ dendritic cells. J. Exp. Med. 207(6), 1261-1271 (2010).
79. Huysamen C, Willment JA, Dennehy KM, Brown GD. CLEC9A is a novel activation C-type lectin-like receptor expressed on BDCA3+ dendritic cells and a subset of monocytes. J. Biol. Chem. 283(24), 16693-16701 (2008).
80. Schreibelt G, Klinkenberg LJ, Cruz LJ et al. The C-type lectin receptor CLEC9A mediates antigen uptake and (cross-) presentation by human blood BDCA3+ myeloid dendritic cells. Blood 119(10), 2284-2292 (2012).
81. Caminschi I, Proietto AI, Ahmet F et al. The dendritic cell subtype-restricted C-type lectin Clec9A is a target for vaccine enhancement. Blood 112(8), 3264-3273 (2008).
82. Mittag D, Proietto AI, Loudovaris T et al. Human dendritic cell subsets from spleen and blood are similar in phenotype and function but modified by donor health status. J. Immunol. 186(11), 6207-6217 (2011).
83. Segura E, Valladeau-Guilemond J, Donnadieu MH, Sastre-Garau X, Soumelis V, Amigorena S. Characterization of resident and migratory dendritic cells in human lymph nodes. J. Exp. Med. 209(4), 653-660 (2012).
84. Colonna M, Cella M. Crosspresentation: plasmacytoid dendritic cells are in the business. Immunity 27(3), 419-421 (2007).
85. Gabrilovich D. Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nature Rev. Immunol. 4(12), 941-952 (2004).
86. Hoffmann TK, Müller-Berghaus J, Ferris RL et al. Alterations in the frequency of dendritic cell subsets in the peripheral circulation of patients with squamous cell carcinomas of the head and neck. Clin. Cancer Res. 8, 1787-1793 (2002).
87. Della Bella S, Gennaro M, Vaccari M et al. Altered maturation of peripheral blood dendritic cells in patients with breast cancer. Br. J. Cancer 89(8), 1463-1472 (2003).
88. Dong R, Cwynarski K, Entwistle A et al. Dendritic cells from CML patients have altered actin organization, reduced antigen processing, and impaired migration. Blood 101(9), 3560-3567 (2003).
89. Mohty M. Circulating blood dendritic cells from myeloid leukemia patients display quantitative and cytogenetic abnormalities as well as functional impairment. Blood 98(13), 3750-3756 (2001).
90. Matteo Rigolin G, Howard J, Buggins A et al. Phenotypic and functional characteristics of monocyte-derived dendritic cells from patients with myelodysplastic syndromes. Br. J. Haematol. 107(4), 844-850 (1999).
91. Ma L, Delforge M, Van Duppen V et al. Circulating myeloid and lymphoid precursor dendritic cells are clonally involved in myelodysplastic syndromes. Leukemia 18(9), 1451-1456 (2004).
92. Micheva I, Thanopoulou E, Michalopoulou S et al. Defective tumor necrosis factor alpha-induced maturation of monocyte-derived dendritic cells in patients with myelodysplastic syndromes. Clin. Immunol. 113(3), 310-317 (2004).
93. Ma L, Ceuppens J, Kasran A, Delforge M, Boogaerts M, Vandenberghe P. Immature and mature monocyte-derived dendritic cells in myelodysplastic syndromes of subtypes refractory anemia or refractory anemia with ringed sideroblasts display an altered cytokine profile. Leuk. Res. 31(10), 1373-1382 (2007).
94. Micheva I, Thanopoulou E, Michalopoulou S et al. Impaired generation of bone marrow CD34-derived dendritic cells with low peripheral blood subsets in patients with myelodysplastic syndrome. Br. J. Haematol. 126(6), 806-814 (2004).
95. Jefford M, Schnurr M, Toy T et al. Functional comparison of DCs generated in vivo with Flt3 ligand or in vitro from blood monocytes: differential regulation of function by specific classes of physiologic stimuli. Blood 102(5), 1753-1763 (2003).
96. Saft L, Bjorklund E, Berg E, Hellstrom-Lindberg E, Porwit A. Bone marrow dendritic cells are reduced in patients with high-risk myelodysplastic syndromes. Leuk. Res. 37(3), 266-273 (2012).
97. Li L, Giannopoulos K, Reinhardt P et al. Immunotherapy for patients with acute myeloid leukemia using autologous dendritic cells generated from leukemic blasts. Int. J. Oncol. 28(4), 855-861 (2006).
98. Litzow M, Dietz A, Bulur P et al. Testing the safety of clinical-grade mature autologous myeloid DC in a Phase I clinical immunotherapy trial of CML. Cytotherapy 8(3), 290-298 (2006).
99. Frank MO, Kaufman J, Tian S et al. Harnessing naturally occurring tumor immunity: a clinical vaccine trial in prostate cancer. PLoS ONE 5(9), 1-12 (2010).
100. Benteyn D, Van Nuffel AM, Wilgenhof S et al. Characterization of CD8+ T-cell responses in the peripheral blood and skin injection sites of melanoma patients treated with mrna electroporated autologous dendritic cells (TriMixDC-MEL). BioMed. Res. Int. 2013, 976383 (2013).
101. Tamir A, Basagila E, Kagahzian A et al. Induction of tumor-specific T-cell responses by vaccination with tumor lysate-loaded dendritic cells in colorectal cancer patients with carcinoembryonic-antigen positive tumors. Cancer Immunol. Immunother. 56(12), 2003-2016 (2007).
102. Pellagatti A, Cazzola M, Giagounidis A et al. Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells. Leukemia 24(4), 756-764 (2010).
103. Boultwood J, Wainscoat JS. Gene silencing by DNA methylation in haematological malignancies. Br. J. Haematol. 138(1), 3-11 (2007).
104. Del Rey M, O'Hagan K, Dellett M et al. Genome-wide profiling of methylation identifies novel targets with aberrant hypermethylation and reduced expression in low-risk myelodysplastic syndromes. Leukemia 27(3), 610-618 (2013).
105. Shen L, Kantarjian H, Guo Y et al. DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes. J. Clin. Oncol. 28(4), 605-613 (2010).
106. Christman JK. 5-Azacytidine and 5-aza-2́-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene 21(35), 5483-5495 (2002).
107. Garcia-Manero G, Fenaux P. Hypomethylating agents and other novel strategies in myelodysplastic syndromes. J. Clin. Oncol. 29(5), 516-523 (2011).
108. Fenaux P, Mufti GJ, Hellstrom-Lindberg E et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, Phase III study. Lancet Oncol. 10(3), 223-232 (2009).
109. Kornblith AB. Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized Phase III trial: a Cancer and Leukemia Group B Study. J. Clin. Oncol. 20(10), 2441-2452 (2002).
110. Agarwal S, Rao A. Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. Immunity 9(6), 765-775 (1998).
111. Jones B, Chen J. Inhibition of IFN-gamma transcription by site-specific methylation during T helper cell development. EMBO J. 25(11), 2443-2452 (2006).
112. Costantini B, Kordasti S, Kulasekararaj AG et al. The effects of 5-azacytidine on the function and number of regulatory T-cells and T-effectors in myelodysplastic syndrome. Haematologica doi:10.3324/haematol.2012.074823 (2012) (Epub ahead of print).
113. Sa LI, Gutierrez-cosio S, Santamaría C et al. Immunomodulatory effect of 5-azacytidine (5-azaC): potential role in the transplantation setting. Blood 115(1), 107-121 (2010).
114. Bontkes HJ, Ruben JM, Alhan C, Westers TM, Ossenkoppele GJ, van de Loosdrecht AA. Azacitidine differentially affects CD4(pos) T-cell polarization in vitro and in vivo in high risk myelodysplastic syndromes. Leuk. Res. 36(7), 921-930 (2012).
115. Frikeche J, Clavert A, Delaunay J et al. Impact of the hypomethylating agent 5-azacytidine on dendritic cells function. Exp. Hematol. 39(11), 1056-1063 (2011).
116. Rosu-Myles M, Taylor BJ, Wolff L. Loss of the tumor suppressor p15Ink4b enhances myeloid progenitor formation from common myeloid progenitors. Exp. Hematol. 35(3), 394-406 (2007).
117. Rosu-Myles M, Wolff L. P15Ink4b: dual function in myelopoiesis and inactivation in myeloid disease. Blood Cells Mol. Dis. 40(3), 406-409 (2008).
118. Quesnel B, Guillerm G, Vereecque R et al. Methylation of the p15(INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression. Blood 91(8), 2985-2990 (1998).
119. Tien HF, Tang JH, Tsay W et al. Methylation of the p15(INK4B) gene in myelodysplastic syndrome: it can be detected early at diagnosis or during disease progression and is highly associated with leukaemic transformation. Br. J. Haematol. 112(1), 148-154 (2001).
120. Fares J, Koller R, Humeniuk R, Wolff L, Bies J. The tumor suppressor p15Ink4b regulates the differentiation and maturation of conventional dendritic cells. Blood 119(21), 5005-5015 (2012).
121. Curik N, Burda P, Vargova K et al. 5-azacitidine in aggressive myelodysplastic syndromes regulates chromatin structure at PU.1 gene and cell differentiation capacity. Leukemia 26(8), 1804-1811 (2012).
122. Daskalakis M, Nguyen TT, Nguyen C et al. Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-aza-2́-deoxycytidine (decitabine) treatment. Blood 100(8), 2957-2964 (2002).
123. Griffiths EA, Gore SD. DNA Methyltransferase and histone deacetylase inhibitors in the treatment of myelodysplastic syndromes. Semin. Hematol. 45(1), 23-30 (2008).
124. Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nature Genet. 21(1), 103-107 (1999).
125. Youn JI, Kumar V, Collazo M et al. Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. Nat. Immunol. 14(3), 211-220 (2013).
126. Frikeche J, Simon T, Brissot E, Grégoire M, Gaugler B, Mohty M. Impact of valproic acid on dendritic cells function. Immunobiology 217(7), 704-710 (2012).
127. Song W, Tai YT, Tian Z et al. HDAC inhibition by LBH589 affects the phenotype and function of human myeloid dendritic cells. Leukemia 25, 161-168 (2011).
128. Nencioni A, Beck J, Werth D et al. Histone deacetylase inhibitors affect dendritic cell differentiation and immunogenicity. Clin. Cancer Res. 13(13), 3933-3941 (2007).
129. Brogdon JL, Xu Y, Szabo SJ et al. Histone deacetylase activities are required for innate immune cell control of Th1 but not Th2 effector cell function. Blood 109(3), 1123-1130 (2007).
130. Moldenhauer A, Frank RC, Pinilla-Ibarz J et al. Histone deacetylase inhibition improves dendritic cell differentiation of leukemic blasts with AML1-containing fusion proteins. J. Leuk. Biol. 76(3), 623-633 (2004).
131. Fenaux P, Giagounidis A, Selleslag D et al. A randomized Phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with low-/intermediate-1-risk myelodysplastic syndromes with del5q. Blood 118(14), 3765-3776 (2011).
132. Le Bras F, Sebert M, Kelaidi C et al. Treatment by Lenalidomide in lower risk myelodysplastic syndrome with 5q deletion-the GFM experience. Leuk. Res. 35(11), 1444-1448 (2011).
133. Mollgård L, Saft L, Treppendahl MB et al. Clinical effect of increasing doses of lenalidomide in high-risk myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities. Haematologica 96(7), 963-971 (2011).
134. Sibon D, Cannas G, Baracco F et al. Lenalidomide in lower-risk myelodysplastic syndromes with karyotypes other than deletion 5q and refractory to erythropoiesis-stimulating agents. Br. J. Haematol. 156(5), 619-625 (2012).
135. Reddy N, Hernandez-Ilizaliturri FJ, Deeb G et al. Immunomodulatory drugs stimulate natural killer-cell function, alter cytokine production by dendritic cells, and inhibit angiogenesis enhancing the anti-tumour activity of rituximab in vivo. Br. J. Haematol. 140(1), 36-45 (2008).
136. Leblanc R, Hideshima T, Catley LP et al. Immunomodulatory drug costimulates T cells via the B7-CD28 pathway. Blood 103(5), 1787-1790 (2004).
137. Galustian C, Meyer B, Keith ML et al. The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells. Cancer Immunol. Immunother. 58, 1033-1045 (2009).
138. Henry JY, Labarthe M-C, Meyer B, Dasgupta P, Dalgleish AG, Galustiano C. Enhanced cross-priming of naive CD8+ T cells by DCs treated by the IMiDs® immunomodulatory compounds lenalidomide and pomalidomide. Immunology doi:10.1111/imm.12087 (2013) (Epub ahead of print).
139. Sekeres MA, Tiu R V, Komrokji R et al. Phase 2 study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syndromes. Blood 120(25), 4945-4951 (2012).
140. Steinbrink K, Wolfl M, Jonuleit H, Knop J, Enk AH. Induction of tolerance by IL 10-treated dendritic cells. J. Immunol. 159, 4772-4780 (1997).
141. Cao W, Bover L, Cho M et al. Regulation of TLR7/9 responses in plasmacytoid dendritic cells by BST2 and ILT7 receptor interaction. J. Exp. Med. 206(7), 1603-1614 (2009).
142. Coukos G, Benencia F, Buckanovich RJ, Conejo-Garcia Jr. The role of dendritic cell precursors in tumour vasculogenesis. Br. J. Cancer 92(7), 1182-1187 (2005).
143. Banchereau J, Palucka AK. Dendritic cells as therapeutic vaccines against cancer. Nature Rev. Immunol. 5(4), 296-306 (2005).
144. Sabado RL, Bhardwaj N. Directing dendritic cell immunotherapy towards successful cancer treatment. Immunotherapy 2(1), 37-56 (2010).
145. Westers TM, Houtenbos I, van de Loosdrecht AA, Ossenkoppele GJ. Principles of dendritic cell-based immunotherapy in myeloid leukemia. Immunobiology 211(6-8), 663-676 (2006).
146. Van den Ancker W, Westers TM, Ossenkoppele GJ, van de Loosdrecht AA. Back to basics: in search of the optimal dendritic cell for vaccination in AML. Leuk. Res. 32(11), 1641-1643 (2008).
147. Greiner J, Ringhoffer M, Taniguchi M et al. mRNA expression of leukemia-associated antigens in patients with acute myeloid leukemia for the development of specific immunotherapies. Int. J. Cancer 108(5), 704-711 (2004).
148. Houtenbos I, Westers TM, Ossenkoppele GJ, Van de Loosdrecht AA. Feasibility of clinical dendritic cell vaccination in acute myeloid leukemia. Immunobiology 211(6-8), 677-685 (2006).
149. Roddie H, Klammer M, Thomas C et al. Phase I/II study of vaccination with dendritic-like leukaemia cells for the immunotherapy of acute myeloid leukaemia. Br. J. Haematol. 133(2), 152-157 (2006).
150. Feller N, Van der Pol MA, Van Stijn a et al. MRD parameters using immunophenotypic detection methods are highly reliable in predicting survival in acute myeloid leukaemia. Leukemia 18(8), 1380-1390 (2004).
151. Westers TM, Stam AG, Scheper RJ et al. Rapid generation of antigen-presenting cells from leukaemic blasts in acute myeloid leukaemia. Cancer Immunol. Immunother. 52(1), 17-27 (2003).
152. Li L, Reinhardt P, Schmitt A et al. Dendritic cells generated from acute myeloid leukemia (AML) blasts maintain the expression of immunogenic leukemia associated antigens. Cancer Immunol. Immunother. 54(7), 685-693 (2005).
153. Westers TM, Houtenbos I, Snoijs NC, van de Loosdrecht AA, Ossenkoppele GJ. Leukemia-derived dendritic cells in acute myeloid leukemia exhibit potent migratory capacity. Leukemia 19(7), 1270-1272 (2005).
154. Harrison BD. Stimulation of autologous proliferative and cytotoxic T-cell responses by 'leukemic dendritic cells' derived from blast cells in acute myeloid leukemia. Blood 97(9), 2764-2771 (2001).
155. Almstedt M, Blagitko-Dorfs N, Duque-Afonso J et al. The DNA demethylating agent 5-aza-2́-deoxycytidine induces expression of NY-ESO-1 and other cancer/testis antigens in myeloid leukemia cells. Leuk. Res. 34(7), 899-905 (2010).
156. Whiteway A, Corbett T, Anderson R, MacDonald I, Prentice HG. Expression of co-stimulatory molecules on acute myeloid leukaemia blasts may effect duration of first remission. Br. J. Haematol. 120(3), 442-451 (2003).
157. Van Luijn MM, Chamuleau ME, Thompson JA et al. Class II-associated invariant chain peptide down-modulation enhances the immunogenicity of myeloid leukemic blasts resulting in increased CD4+ T-cell responses. Haematologica 95(3), 485-493 (2010).
158. Chan L, Hardwick N, Darling D et al. IL 2/B7.1 (CD80) fusagene transduction of AML blasts by a self-inactivating lentiviral vector stimulates T cell responses in vitro: a strategy to generate whole cell vaccines for AML. Mol. Ther. 11(1), 120-131 (2005).
159. Ingram W, Chan L, Darling D, Hardwick N. Human CD80/IL2 lentivirus-transduced acute myeloid leukaemia (AML) cells promote natural killer (NK) cell activation and cytolytic activity: implications for a Phase I clinical study. Br. J. Haematol. 145, 749-760 (2009).
160. Hardwick N, Chan L, Ingram W, Mufti G, Farzaneh F. Lytic activity against primary AML cells is stimulated in vitro by an autologous whole cell vaccine expressing IL 2 and CD80. Cancer Immunol. Immunother. 59(3), 379-388 (2010).
161. Kremser A, Dressig J, Grabrucker C et al. Dendritic cells (DCs) can be successfully generated from leukemic blasts in individual patients with AML or MDS: an evaluation of different methods. J. Immunother. 33(2), 185-199 (2010).
162. Kufner S, Fleischer RP, Kroell T et al. Serum-free generation and quantification of functionally active leukemia-derived DC is possible from malignant blasts in acute myeloid leukemia and myelodysplastic syndromes. Cancer Immunol. Immunother. 54(10), 953-970 (2005).
163. Grabrucker C, Liepert A, Dreyig J et al. The quality and quantity of leukemia-derived dendritic cells from patients with acute myeloid leukemia and myelodysplastic syndrome are a predictive factor for the lytic potential of dendritic cells-primed leukemia-specific T cells. J. Immunother. 33(5), 523-537 (2010).
164. Bruder D, Westendorf AM, Hansen W et al. On the edge of autoimmunity T-cell stimulation by steady-state dendritic cells prevents autoimmune diabetes. Diabetes 54, 3395-3401 (2005).
165. Yamazaki S, Dudziak D, Heidkamp GF et al. CD8+ CD205+ Foxp3+ splenic dendritic cells are specialized to induce regulatory T cells. J. Immunol. 181(10), 1-24 (2008).
166. Kato M, McDonald KJ, Khan S et al. Expression of human DEC-205 (CD205) multilectin receptor on leukocytes. Int. Immunol. 18(6), 857-869 (2006).
167. Lahoud MH, Ahmet F, Kitsoulis S et al. Targeting antigen to mouse dendritic cells via Clec9A induces potent CD4 T cell responses biased toward a follicular helper phenotype. J. Immunol. 187(2), 842-850 (2011).
168. Sancho D, Mourao-sa D, Joffre OP et al. Tumor therapy in mice via antigen targeting to a novel, DC-restricted C-type lectin. J. Clin. Invest. 118(6), 2098-2110 (2008).
169. Aggarwal S, Van de Loosdrecht AA, Alhan C, Ossenkoppele GJ, Westers TM, Bontkes HJ. Role of immune responses in the pathogenesis of low-risk MDS and high-risk MDS: implications for immunotherapy. Br. J. Haematol. 153(5), 568-581 (2011).
170. Greenberg PL, Cox C, LeBeau MM et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89(6), 2079-2088 (1997).
171. Leukemic dendritic cell vaccination in patients with acute myeloid leukemia. http://clinicaltrials.gov/show/NCT01373515
172. Decitabine and vaccine therapy for patients with relapsed AML following allogeneic stem cell transplantation. http://clinicaltrials.gov/show/NCT01483274
173. Lentivirus transduced acute myeloid leukaemia blasts expressing B7.1 (CD80) and IL-2 (RFUSIN2-AML1). http://clinicaltrials.gov/show/NCT00718250