Seminars in Hematology
Volume 45, Issue 1 , Pages 39-48 , January 2008

The Role of the Immune System in Myelodysplasia: Implications for Therapy

  • Elaine M. Sloand

      Affiliations

    • Corresponding Author InformationAddress correspondence to Elaine M. Sloand, MD, National Heart Lung and Blood Institute, Hematology Branch, Building 10 CRC, 4E Room 5230, Bethesda, MD 20892.
  • ,
  • Katayoun Rezvani

References 

  1. Albanese C, D’Amico M, Reutens AT, et al. Activation of the cyclin D1 gene by the E1A-associated protein p300 through AP-1 inhibits cellular apoptosis. J Biol Chem. 1999;274:34186–34195
  2. Deeg HJ, Beckham C, Loken MR, et al. Negative regulators of hemopoiesis and stroma function in patients with myelodysplastic syndrome. Leuk Lymphoma. 2000;37:405–414
  3. Mufti G, List AF, Gore SD, Ho AYL. Myelodysplastic syndrome. Hematology. 2003;2003:176–199
  4. Parker JE, Mufti GJ. The role of apoptosis in the pathogenesis of the myelodysplastic syndromes. Int J Hematol. 2001;73:416–428
  5. Parker JE, Mufti GJ. Excessive apoptosis in low risk myelodysplastic syndromes (MDS). Leuk Lymphoma. 2000;40:1–24
  6. Parker JE, Mufti GJ, Rasool F, et al. The role of apoptosis, proliferation, and the Bcl-2-related proteins in the myelodysplastic syndromes and acute myeloid leukemia secondary to MDS. Blood. 2000;96:3932–3938
  7. Parker JE, Fishlock KL, Mijovic A, et al. ’Low-risk’ myelodysplastic syndrome is associated with excessive apoptosis and an increased ratio of pro- versus anti-apoptotic bcl-2-related proteins. Br J Haematol. 1998;103:1075–1082
  8. Parker JE, Mufti GJ. Ineffective haemopoiesis and apoptosis in myelodysplastic syndromes. Br J Haematol. 1998;101:220–230
  9. Aivado M, Gattermann N, Bottomley S. X chromosome inactivation ratios in female carriers of X-linked sideroblastic anemia. Blood. 2001;97:4000–4002
  10. Cocca BA, Cline AM, Radic MZ. Blebs and apoptotic bodies are B cell autoantigens. J Immunol. 2002;169:159–166
  11. Kokhaei P, Choudhury A, Mahdian R, et al. Apoptotic tumor cells are superior to tumor cell lysate, and tumor cell RNA in induction of autologous T cell response in B-CLL. Leukemia. 2004;18:1810–1815
  12. Michalopoulou S, Micheva I, Kouraklis-Symeonidis A, et al. Impaired clonogenic growth of myelodysplastic bone marrow progenitors in vitro is irrelevant to their apoptotic state. Leuk Res. 2004;28:805–812
  13. Sloand EM, Pfannes L, Chen G, et al. CD34 cells from patients with trisomy 8 myelodysplastic syndrome (MDS) express early apoptotic markers but avoid programmed cell death by up-regulation of antiapoptotic proteins. Blood. 2007;109:2399–2405
  14. Baumann I, Scheid C, Koref MS, et al. Autologous lymphocytes inhibit hemopoiesis in long-term culture in patients with myelodysplastic syndrome. Exp Hematol. 2002;30:1405–1411
  15. Molldrem JJ, Jiang YZ, Stetler-Stevenson M, et al. Haematological response of patients with myelodysplastic syndrome to antithymocyte globulin is associated with a loss of lymphocyte-mediated inhibition of CFU-GM and alterations in T-cell receptor Vbeta profiles. Br J Haematol. 1998;102:1314–1322
  16. Sloand EM, Mainwaring L, Fuhrer M, et al. Preferential suppression of trisomy 8 compared with normal hematopoietic cell growth by autologous lymphocytes in patients with trisomy 8 myelodysplastic syndrome. Blood. 2005;106:841–851
  17. Kochenderfer JN, Kobayashi S, Wieder ED, Su C, Molldrem JJ. Loss of T-lymphocyte clonal dominance in patients with myelodysplastic syndrome responsive to immunosuppression. Blood. 2002;100:3639–3645
  18. Melenhorst JJ, Eniafe R, Follmann D, et al. Molecular and flow cytometric characterization of the CD4 and CD8 T-cell repertoire in patients with myelodysplastic syndrome. Br J Haematol. 2002;119:97–105
  19. Epperson DE, Nakamura R, Saunthararajah Y, Melenhorst J, Barrett AJ. Oligoclonal T cell expansion in myelodysplastic syndrome: evidence for an autoimmune process. Leuk Res. 2001;25:1075–1083
  20. Plasilova M, Risitano A, Maciejewski JP. Application of the molecular analysis of the T-cell receptor repertoire in the study of immune-mediated hematologic diseases. Hematology. 2003;8:173–181
  21. Barrett J, Saunthararajah Y, Molldrem J. Myelodysplastic syndrome and aplastic anemia: Distinct entities or diseases linked by a common pathophysiology?. Semin Hematol. 2000;37:15–29
  22. Sloand EM, Kim S, Fuhrer M, et al. Fas-mediated apoptosis is important in regulating cell replication and death in trisomy 8 hematopoietic cells but not in cells with other cytogenetic abnormalities. Blood. 2002;100:4427–4432
  23. Risitano AM, Maciejewski JP, Muranski P, et al. Large granular lymphocyte (LGL)-like clonal expansions in paroxysmal nocturnal hemoglobinuria (PNH) patients. Leukemia. 2005;19:217–222
  24. Maciejewski J, Selleri C, Anderson S, Young NS. Fas antigen expression on CD34+ human marrow cells is induced by interferon gamma and tumor necrosis factor alpha and potentiates cytokine-mediated hematopoietic suppression in vitro. Blood. 1995;85:3183–3190
  25. Koike M, Ishiyama T, Tomoyasu S, Tsuruoka N. Spontaneous cytokine overproduction by peripheral blood mononuclear cells from patients with myelodysplastic syndromes and aplastic anemia. Leuk Res. 1995;19:639–644
  26. Kitagawa M, Saito I, Kuwata T, et al. Overexpression of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma by bone marrow cells from patients with myelodysplastic syndromes. Leukemia. 1997;11:2049–2054
  27. Zang DY, Goodwin RG, Loken MR, Bryant E, Deeg HJ. Expression of tumor necrosis factor-related apoptosis-inducing ligand, Apo2L, and its receptors in myelodysplastic syndrome: Effects on in vitro hemopoiesis. Blood. 2001;98:3058–3065
  28. Kitagawa M, Saito I, Kuwata T, et al. Overexpression of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma by bone marrow cells from patients with myelodysplastic syndromes. Leukemia. 1997;11:2049–2054
  29. Deeg HJ, Gotlib J, Beckham C, et al. Soluble TNF receptor fusion protein (etanercept) for the treatment of myelodysplastic syndrome: a pilot study. Leukemia. 2002;16:162–164
  30. Bouscary D, De Vos J, Guesnu M, et al. Fas/Apo-1 (CD95) expression and apoptosis in patients with myelodysplastic syndromes. Leukemia. 1997;11:839–845
  31. Kitagawa M, Yamaguchi S, Takahashi M, et al. Localization of Fas and Fas ligand in bone marrow cells demonstrating myelodysplasia. Leukemia. 1998;12:486–492
  32. Lepelley P, Grardel N, Emy O, et al. Fas/APO-1 (CD95) expression in myelodysplastic syndromes. Leuk Lymphoma. 1998;30:307–312
  33. Gupta P, Niehans GA, LeRoy SC, et al. Fas ligand expression in the bone marrow in myelodysplastic syndromes correlates with FAB subtype and anemia, and predicts survival. Leukemia. 1999;13:44–53
  34. Claessens YE, Bouscary D, Dupont JM, et al. In vitro proliferation and differentiation of erythroid progenitors from patients with myelodysplastic syndromes: Evidence for Fas-dependent apoptosis. Blood. 2002;99:1594–1601
  35. Zang DY, Goodwin RG, Loken MR, Bryant E, Deeg HJ. Expression of tumor necrosis factor-related apoptosis-inducing ligand, Apo2L, and its receptors in myelodysplastic syndrome: Effects on in vitro hemopoiesis. Blood. 2001;98:3058–3065
  36. Sawanobori M, Yamaguchi S, Hasegawa M, et al. Expression of TNF receptors and related signaling molecules in the bone marrow from patients with myelodysplastic syndromes. Leuk Res. 2003;27:583–591
  37. Barkett M, Gilmore TD. Control of apoptosis by Rel/NF-kappaB transcription factors. Oncogene. 1999;18:6910–6924
  38. Chen G, Zeng W, Miyazato A, et al. Distinctive gene expression profiles of CD34 cells from patients with myelodysplastic syndrome characterized by specific chromosomal abnormalities. Blood. 2004;
  39. Call KM, Glaser T, Ito CY, et al. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms’ tumor locus. Cell. 1990;60:509–520
  40. Haber DA, Buckler AJ. WT1: A novel tumor suppressor gene inactivated in Wilms’ tumor. New Biol. 1992;4:97–106
  41. Haber DA, Housman DE. Role of the WT1 gene in Wilms’ tumour. Cancer Surv. 1992;12:105–117
  42. Park S, Schalling M, Bernard A, et al. The Wilms tumour gene WT1 is expressed in murine mesoderm-derived tissues and mutated in a human mesothelioma. Nat Genet. 1993;4:415–420
  43. Boublikova L, Kalinova M, Ryan J, et al. Wilms’ tumor gene 1 (WT1) expression in childhood acute lymphoblastic leukemia: A wide range of WT1 expression levels, its impact on prognosis and minimal residual disease monitoring. Leukemia. 2006;20:254–263
  44. Brieger J, Weidmann E, Fenchel K, et al. The expression of the Wilms’ tumor gene in acute myelocytic leukemias as a possible marker for leukemic blast cells. Leukemia. 1994;8:2138–2143
  45. Cilloni D, Gottardi E, Messa F, et al. Significant correlation between the degree of WT1 expression and the International Prognostic Scoring System Score in patients with myelodysplastic syndromes. J Clin Oncol. 2003;21:1988–1995
  46. Inoue K, Sugiyama H, Ogawa H, et al. WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. Blood. 1994;84:3071–3079
  47. Inoue K, Ogawa H, Sonoda Y, et al. Aberrant overexpression of the Wilms tumor gene (WT1) in human leukemia. Blood. 1997;89:1405–1412
  48. Menssen HD, Renkl HJ, Rodeck U, et al. Presence of Wilms’ tumor gene (wt1) transcripts and the WT1 nuclear protein in the majority of human acute leukemias. Leukemia. 1995;9:1060–1067
  49. Niegemann E, Wehner S, Kornhuber B, Schwabe D, Ebener U. wt1 gene expression in childhood leukemias. Acta Haematol. 1999;102:72–76
  50. Ostergaard M, Olesen LH, Hasle H, Kjeldsen E, Hokland P. WT1 gene expression: An excellent tool for monitoring minimal residual disease in 70% of acute myeloid leukaemia patients—Results from a single-centre study. Br J Haematol. 2004;125:590–600
  51. Sugiyama H. Wilms tumor gene WT1 as a tumor marker for leukemic blast cells and its role in leukemogenesis. Methods Mol Med. 2002;68:223–237
  52. Tamaki H, Ogawa H, Ohyashiki K, et al. The Wilms’ tumor gene WT1 is a good marker for diagnosis of disease progression of myelodysplastic syndromes. Leukemia. 1999;13:393–399
  53. Shichishima T, Okamoto M, Ikeda K, et al. HLA class II haplotype and quantitation of WT1 RNA in Japanese patients with paroxysmal nocturnal hemoglobinuria. Blood. 2002;100:22–28
  54. Inoue K, Sugiyama H, Ogawa H, et al. WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. Blood. 1994;84:3071–3079
  55. Tamaki H, Ogawa H, Ohyashiki K, et al. The Wilms’ tumor gene WT1 is a good marker for diagnosis of disease progression of myelodysplastic syndromes. Leukemia. 1999;13:393–399
  56. Cilloni D, Gottardi E, Messa F, et al. Significant correlation between the degree of WT1 expression and the International Prognostic Scoring System Score in patients with myelodysplastic syndromes. J Clin Oncol. 2003;21:1988–1995
  57. Li Z, Oka Y, Tsuboi A, et al. WT1(235), a ninemer peptide derived from Wilms’ tumor gene product, is a candidate peptide for the vaccination of HLA-A*0201-positive patients with hematopoietic malignancies. Int J Hematol. 2005;82:458–459
  58. Chen G, Zeng W, Miyazato A, et al. Distinctive gene expression profiles of CD34 cells from patients with myelodysplastic syndrome characterized by specific chromosomal abnormalities. Blood. 2004;104:4210–4218
  59. Molldrem J, Dermime S, Parker K, et al. Targeted T-cell therapy for human leukemia: cytotoxic T lymphocytes specific for a peptide derived from proteinase 3 preferentially lyse human myeloid leukemia cells. Blood. 1996;88:2450–2457
  60. Scheibenbogen C, Letsch A, Thiel E, et al. CD8 T-cell responses to Wilms tumor gene product WT1 and proteinase 3 in patients with acute myeloid leukemia. Blood. 2002;100:2132–2137
  61. Molldrem JJ, Lee PP, Wang C, Champlin RE, Davis MM. A PR1-human leukocyte antigen-A2 tetramer can be used to isolate low-frequency cytotoxic T lymphocytes from healthy donors that selectively lyse chronic myelogenous leukemia. Cancer Res. 1999;59:2675–2681
  62. Molldrem J, Dermime S, Parker K, et al. Targeted T-cell therapy for human leukemia: Cytotoxic T lymphocytes specific for a peptide derived from proteinase 3 preferentially lyse human myeloid leukemia cells. Blood. 1996;88:2450–2457
  63. Molldrem JJ, Clave E, Jiang YZ, et al. Cytotoxic T lymphocytes specific for a nonpolymorphic proteinase 3 peptide preferentially inhibit chronic myeloid leukemia colony-forming units. Blood. 1997;90:2529–2534
  64. Rezvani K, Grube M, Brenchley JM, et al. Functional leukemia-associated antigen-specific memory CD8+ T cells exist in healthy individuals and in patients with chronic myelogenous leukemia before and after stem cell transplantation. Blood. 2003;102:2892–2900
  65. Scheibenbogen C, Letsch A, Thiel E, et al. CD8 T-cell responses to Wilms tumor gene product WT1 and proteinase 3 in patients with acute myeloid leukemia. Blood. 2002;100:2132–2137
  66. Rezvani K, Price D, Brenchley J, et al. Transfer of PR1-specific T-cell clones from donor to recipient by stem cell transplantation and association with GvL activity. Cytotherapy. 2007;9:245–251
  67. Molldrem JJ, Leifer E, Bahceci E, et al. Antithymocyte globulin for treatment of the bone marrow failure associated with myelodysplastic syndromes. Ann Intern Med. 2002;137:156–163
  68. Molldrem JJ, Caples M, Mavroudis D, et al. Antithymocyte globulin for patients with myelodysplastic syndrome. Br J Haematol. 1997;99:699–705
  69. Jonasova A, Neuwirtova R, Cermak J, et al. Cyclosporin A therapy in hypoplastic MDS patients and certain refractory anaemias without hypoplastic bone marrow. Br J Haematol. 1998;100:304–309
  70. Killick SB, Mufti G, Cavenagh JD, et al. A pilot study of antithymocyte globulin (ATG) in the treatment of patients with ’low-risk’ myelodysplasia. Br J Haematol. 2003;120:679–684
  71. Yazji S, Giles FJ, Tsimberidou AM, et al. Antithymocyte globulin (ATG)-based therapy in patients with myelodysplastic syndromes. Leukemia. 2003;17:2101–2106
  72. Grigg AP, O’Flaherty E. Cyclosporin A for the treatment of pure red cell aplasia associated with myelodysplasia. Leuk Lymphoma. 2001;42:1339–1342
  73. Catalano L, Selleri C, Califano C, et al. Prolonged response to cyclosporin-A in hypoplastic refractory anemia and correlation with in vitro studies. Haematologica. 2000;85:133–138
  74. Atoyebi W, Bywater L, Rawlings L, Brunskill S, Littlewood TJ. Treatment of myelodysplasia with oral cyclosporin. Clin Lab Haematol. 2002;24:211–214
  75. Shimamoto T, Tohyama K, Okamoto T, et al. Cyclosporin A therapy for patients with myelodysplastic syndrome: Multicenter pilot studies in Japan. Leuk Res. 2003;27:783–788
  76. Shimamoto T, Ohyashiki K. Immunosuppressive treatments for myelodysplastic syndromes. Leuk Lymphoma. 2003;44:593–604
  77. Aivado M, Rong A, Stadler M, et al. Favourable response to antithymocyte or antilymphocyte globulin in low-risk myelodysplastic syndrome patients with a ’non-clonal’ pattern of X-chromosome inactivation in bone marrow cells. Eur J Haematol. 2002;68:210–216
  78. Steensma DP, Dispenzieri A, Moore SB, Schroeder G, Tefferi A. Antithymocyte globulin has limited efficacy and substantial toxicity in unselected anemic patients with myelodysplastic syndrome. Blood. 2003;101:2156–2158
  79. Barrett AJ, Saunthararajah Y, Molldrem J. Myelodysplastic syndrome and aplastic anemia: distinct entities or diseases linked by a common pathophysiology?. Semin Hematol. 2001;37:15–29
  80. Geary CG, Harrison CJ, Philpott NJ, et al. Abnormal cytogenetic clones in patients with aplastic anaemia: Response to immunosuppressive therapy. Br J Haematol. 1999;104:271–274
  81. Broliden PA, Dahl IM, Hast R, et al. Antithymocyte globulin and cyclosporine A as combination therapy for low-risk non-sideroblastic myelodysplastic syndromes. Haematologica. 2006;91:667–670
  82. Gutierrez-Dalmau A, Campistol JM. The role of proliferation signal inhibitors in post-transplant malignancies. Nephrol Dial Transplant. 2007;22:i11–i16
  83. Vincenti F, Ramos E, Brattstrom C, et al. Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation. Transplantation. 2001;71:1282–1287
  84. Jilg W, Hannig K. Lymphocyte surface proteins recognized by an anti-thymocyte-globulin. Hoppe Seylers Z Physiol Chem. 1981;362:1475–1485
  85. Haidinger M, Geyeregger R, Poglitsch M, et al. Antithymocyte globulin impairs T-cell/antigen-presenting cell interaction: Disruption of immunological synapse and conjugate formation. Transplantation. 2007;84:117–121
  86. Lopez M, Clarkson MR, Albin M, Sayegh MH, Najafian N. A novel mechanism of action for anti-thymocyte globulin: Induction of CD4+CD25+Foxp3+ regulatory T cells. J Am Soc Nephrol. 2006;17:2844–2853
  87. Barrett AJ, Molldrem JJ, Saunthrajarian Y, Caples M, Young NS. Prolonged tranfusion independence and disease stability in patients with myelodysplastic syndrome (MDS) responding to antithymocyte glogulin (ATG). Blood. 1998;10(suppl 1, abstr):713a
  88. Sloand EM, Wu CO, Greenberg P, Young NS, Barrett J: Prolonged survival in patients with myelodysplasia responding to immunosuppressive therapy. J Clin Oncol (in press)
  89. Frickhofen N. Aplastic Anemia: Current Perspectives on the Pathogenesis and Treatment. In:  Raghavachar A,  Schrezenmeier H,  Frickhofen N editor. Antilymphocyte globulin and methylprednisolone with or without cyclosporine A for treatment of aplastic anemia (Updated results of a German randomized trial). Vienna, Austria: Blackwell-MZV; 1993;p. 118–125
  90. Zheng Y, Liu Y, Chu Y. Immunosuppressive therapy for acquired severe aplastic anemia (SAA): A prospective comparison of four different regimens. Exp Hematol. 2006;34:826–831
  91. Stadler M, Germing U, Kliche KO, et al. A prospective, randomised, phase II study of horse antithymocyte globulin vs rabbit antithymocyte globulin as immune-modulating therapy in patients with low-risk myelodysplastic syndromes. Leukemia. 2004;18:460–465
  92. Lim ZY, Killick S, Germing U, et al. Low IPSS score and bone marrow hypocellularity in MDS patients predict hematological responses to antithymocyte globulin. Leukemia. 2007;21:1436–1441
  93. Cheson BD, Bennett JM, Kantarjian H, et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000;96:3671–3674
  94. Saunthararajah Y, Nakamura R, Wesley R, Wang QJ, Barrett AJ. A simple method to predict response to immunosuppressive therapy in patients with myelodysplastic syndrome. Blood. 2003;102:3025–3027
  95. Yue G, Hao S, Fadare O, et al: Hypocellularity in myelodysplastic syndrome is an independent factor which predicts a favorable outcome. Leuk Res (in press)
  96. Ma X, Does M, Raza A, Mayne ST. Myelodysplastic syndromes: Incidence and survival in the United States. Cancer. 2007;109:1536–1542
  97. Maciejewski JP, Risitano A, Sloand EM, Nunez O, Young NS. Distinct clinical outcomes for cytogenetic abnormalities evolving from aplastic anemia. Blood. 2002;99:3129–3135
  98. Musto P. Thalidomide therapy for myelodysplastic syndromes: Current status and future perspectives. Leuk Res. 2004;28:325–332
  99. Moreno-Aspitia A, Colon-Otero G, Hoering A, et al. North Central Cancer Treatment Group Thalidomide therapy in adult patients with myelodysplastic syndrome. Cancer. 2006;107:767–772
  100. Strupp C, Germing U, Aivado M, et al. Thalidomide for the treatment of patients with myelodysplastic syndromes. Leukemia. 2002;16:1–6
  101. Pellagatti A, Jadersten M, Forsblom AM, et al. Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q- syndrome patients. Proc Natl Acad Sci U S A. 2007;104:11406–11411
  102. List A, Kurtin S, Roe DJ, et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005;352:549–557
  103. Raza A, Reeves JA, Feldman EJ, et al: Phase II study of lenalidomide in transfusion-dependent, low- and intermediate-1-risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood (in press)
  104. Maciejewski JP, Risitano AM, Sloand EM, et al. A pilot study of the recombinant soluble human tumour necrosis factor receptor (p75)-Fc fusion protein in patients with myelodysplastic syndrome. Br J Haematol. 2002;117:119–126
  105. Deeg HJ, Jiang PY, Holmberg LA, et al. Hematologic responses of patients with MDS to antithymocyte globulin plus etanercept correlate with improved flow scores of marrow cells. Leuk Res. 2004;28:1177–1180
  106. Kerbauy DM, Lesnikov V, Abbasi N, et al. NF-kappaB and FLIP in arsenic trioxide (ATO)-induced apoptosis in myelodysplastic syndromes (MDSs). Blood. 2005;106:3917–3925
  107. Raza A, Buonamici S, Lisak L, et al. Arsenic trioxide and thalidomide combination produces multi-lineage hematological responses in myelodysplastic syndromes patients, particularly in those with high pre-therapy EVI1 expression. Leuk Res. 2004;28:791–803
  108. List A. Trisenox (arsenic trioxide) in patients with myelodysplastic syndromes (MDS): Preliminary findings in a phase II clinical study. Blood. 2003;2:423a;(abstr)
  109. Gao L, Bellantuono I, Elsasser A, et al. Selective elimination of leukemic CD34(+) progenitor cells by cytotoxic T lymphocytes specific for WT1. Blood. 2000;95:2198–2203
  110. Ohminami H, Yasukawa M, Fujita S. HLA class I-restricted lysis of leukemia cells by a CD8(+) cytotoxic T-lymphocyte clone specific for WT1 peptide. Blood. 2000;95:286–293
  111. Gao L, Bellantuono I, Elsasser A, et al. Selective elimination of leukemic CD34(+) progenitor cells by cytotoxic T lymphocytes specific for WT1. Blood. 2000;95:2198–2203
  112. Ohminami H, Yasukawa M, Fujita S. HLA class I-restricted lysis of leukemia cells by a CD8(+) cytotoxic T-lymphocyte clone specific for WT1 peptide. Blood. 2000;95:286–293
  113. Hosen N, Sonoda Y, Oji Y, et al. Very low frequencies of human normal CD34+ haematopoietic progenitor cells express the Wilms’ tumour gene WT1 at levels similar to those in leukaemia cells. Br J Haematol. 2002;116:409–420
  114. Gaiger A, Reese V, Disis ML, Cheever MA. Immunity to WT1 in the animal model and in patients with acute myeloid leukemia. Blood. 2000;96:1480–1489
  115. Oka Y, Elisseeva OA, Tsuboi A, et al. Human cytotoxic T-lymphocyte responses specific for peptides of the wild-type Wilms’ tumor gene (WT1) product. Immunogenetics. 2000;51:99–107
  116. Tsuboi A, Oka Y, Ogawa H, et al. Cytotoxic T-lymphocyte responses elicited to Wilms’ tumor gene WT1 product by DNA vaccination. J Clin Immunol. 2000;20:195–202
  117. Fraizer GC, Patmasiriwat P, Zhang X, Saunders GF. Expression of the tumor suppressor gene WT1 in both human and mouse bone marrow. Blood. 1995;86:4704–4706
  118. Mailander V, Scheibenbogen C, Thiel E, et al. Complete remission in a patient with recurrent acute myeloid leukemia induced by vaccination with WT1 peptide in the absence of hematological or renal toxicity. Leukemia. 2004;18:165–166
  119. Oka Y, Tsuboi A, Murakami M, et al. Wilms tumor gene peptide-based immunotherapy for patients with overt leukemia from myelodysplastic syndrome (MDS) or MDS with myelofibrosis. Int J Hematol. 2003;78:56–61
  120. Oka Y, Tsuboi A, Taguchi T, et al. Induction of WT1 (Wilms’ tumor gene)-specific cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regression. Proc Natl Acad Sci U S A. 2004;101:13885–13890
  121. Morita S, Oka Y, Tsuboi A, et al. A phase I/II trial of a WT1 (Wilms’ tumor gene) peptide vaccine in patients with solid malignancy: Safety assessment based on the phase I data. Jpn J Clin Oncol. 2006;36:231–236
  122. Kawakami M, Oka Y, Tsuboi A, et al. Clinical and immunologic responses to very low-dose vaccination with WT1 peptide (5 mug/body) in a patient with chronic myelomonocytic leukemia. Int J Hematol. 2007;85:426–429
  123. Oka Y, Tsuboi A, Taguchi T, et al. Induction of WT1 (Wilms’ tumor gene)-specific cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regression. Proc Natl Acad Sci U S A. 2004;101:13885–13890
  124. Molldrem JJ, Lee PP, Wang C, et al. A PR1-human leukocyte antigen-A2 tetramer can be used to isolate low-frequency cytotoxic T lymphocytes from healthy donors that selectively lyse chronic myelogenous leukemia. Cancer Res. 1999;59:2675–2681
  125. Yamada T, Tsurumi H, Kasahara S, et al. Immunosuppressive therapy for myelodysplastic syndrome: Efficacy of methylprednisolone pulse therapy with or without cyclosporin A. J Cancer Res Clin Oncol. 2003;129:485–491
  126. Saunthararajah Y, Nakamura R, Nam JM, et al. HLA-DR15 (DR2) is overrepresented in myelodysplastic syndrome and aplastic anemia and predicts a response to immunosuppression in myelodysplastic syndrome. Blood. 2002;100:1570–1574

PII: S0037-1963(07)00163-1

doi: 10.1053/j.seminhematol.2007.11.006

Seminars in Hematology
Volume 45, Issue 1 , Pages 39-48 , January 2008