International Journal of Hematology

, Volume 73, Issue 4, pp 416–428 | Cite as

The Role of Apoptosis in the Pathogenesis of the Myelodysplastic Syndromes

  • Jane E. Parker
  • Ghulam J. Mufti
Progress in hematology


The paradoxical occurrence of peripheral cytopenias despite a normo/hypercellular marrow in myelodysplastic syndromes (MDS) has been attributed to excessive intramedullary hematopoietic cell apoptosis. It has also been postulated that abrogation of programmed cell death (PCD) may underlie MDS transformation to acute myeloid leukemia (AML). Despite overwhelming evidence for a role of aberrant apoptosis in myelodysplasia, the molecular mechanisms responsible for such changes have not been elucidated. This paper summarizes current evidence implicating a role for altered PCD in MDS and outlines potential cellular mechanisms whereby hematopoietic progenitor cell apoptosis may be dysregulated.

Key words

Apoptosis MDS AML Fas Bcl-2 


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  1. 1.
    Mufti GJ, Galton DA. Myelodysplastic syndromes: natural history and features of prognostic importance.Clin Haematol. 1986;15:953–971.PubMedGoogle Scholar
  2. 2.
    Yoshida Y. Hypothesis: apoptosis may be the mechanism responsible for the premature intramedullary cell death in the myelodys-plastic syndrome.Leukemia. 1993;7:144–146.PubMedGoogle Scholar
  3. 3.
    Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics.Br J Cancer. 1972;26:239–257.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages.J Immunol. 1992;148:2207–2216.PubMedGoogle Scholar
  5. 5.
    Martin SJ, Cotter TG. Ultraviolet B irradiation of human leukemia HL-60 cells in vitro induces apoptosis.Int J Radiat Biol. 1991;59:1001–1016.CrossRefPubMedGoogle Scholar
  6. 6.
    Hickman JA. Apoptosis induced by anticancer drugs.Cancer Metast Rev. 1992;11:121–139.CrossRefGoogle Scholar
  7. 7.
    Laster SM, Wood JG, Gooding LR. Tumor necrosis factor can induce both apoptic and necrotic forms of cell lysis.J Immunol. 1988;141:2629–2634.PubMedGoogle Scholar
  8. 8.
    Suda T, Takahashi T, Golstein P, Nagata S. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family.Cell. 1993;75:1169–1178.PubMedCrossRefGoogle Scholar
  9. 9.
    Williams GT, Smith CA, Spooncer E, Dexter TM, Taylor DR. Haemopoietic colony stimulating factors promote cell survival by suppressing apoptosis.Nature. 1990;343:76–79.PubMedCrossRefGoogle Scholar
  10. 10.
    Thornberry NA, Lazebnik Y. Caspases: enemies within.Science. 1998;281:1312–1316.PubMedCrossRefGoogle Scholar
  11. 11.
    Muzio M, Chinnaiyan AM, Kischkel FC, et al. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex.Cell. 1996;85:817–827.PubMedCrossRefGoogle Scholar
  12. 12.
    Boldin MP, Goncharov TM, Goltsev YV, Wallach D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death.Cell. 1996;85:803–815.PubMedCrossRefGoogle Scholar
  13. 13.
    Li P, Nijhawan D, Budihardjo I, et al. Cytochome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade.Cell. 1997;91:479–489.PubMedCrossRefGoogle Scholar
  14. 14.
    Pan G, Humke EW, Dixit VM. Activation of caspases triggered by cytochrome c in vitro.FEBS Lett. 1998;426:151–154.PubMedCrossRefGoogle Scholar
  15. 15.
    Nakagawa T, Zhu H, Morishima N, et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta.Nature. 2000;403:98–103.PubMedCrossRefGoogle Scholar
  16. 16.
    Earnshaw WC, Martins LM, Kaufmann SH. Mammalian caspases: structure, activation, substrates and functions during apoptosis.Ann Rev Biochem. 1999;68:383–424.PubMedCrossRefGoogle Scholar
  17. 17.
    Nagata S, Golstein P. The Fas death factor.Science. 1995;267:1449–1456.PubMedCrossRefGoogle Scholar
  18. 18.
    Itoh N, Nagata S. A novel protein domain required for apoptosis. Mutational analysis of human Fas antigen.J Biol Chem. 1993;268:10932–10937.PubMedGoogle Scholar
  19. 19.
    Banner DW, D’Arcy A, Janes W, et al. Crystal structure of the soluble human 55 kd TNF receptor-human TNF beta complex: implications for TNF receptor activation.Cell. 1993;73:431–435.PubMedCrossRefGoogle Scholar
  20. 20.
    Chinnaiyan AM, O’Rourke K, Tewari M, Dixit VM. FADD,a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis.Cell. 1995;81:505–512.PubMedCrossRefGoogle Scholar
  21. 21.
    Hsu H, Xiong J, Goeddel DV. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation.Cell. 1995;81:495–504.PubMedCrossRefGoogle Scholar
  22. 22.
    Hsu H, Huang J, Shu HB, Baichwal V, Goeddel DV. TNF-depend-ent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex.Immunity. 1996;4:387–396.PubMedCrossRefGoogle Scholar
  23. 23.
    Hsu H, Shu HB, Pan MG, Goeddel DV. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways.Cell. 1996;84:299–308.PubMedCrossRefGoogle Scholar
  24. 24.
    Kischkel FC, Hellbardt S, Behrmann I, et al. Cytotoxicity-depend-ent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor.EMBO J. 1995;14:5579–5588.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Binder C, Schulz M, Hiddemann W, Oellerich M. Capsase activation and induction of inducible nitric oxide-synthase during TNF alpha-triggered apoptosis.Anticancer Res. 1999;19:1715–1720.PubMedGoogle Scholar
  26. 26.
    Green DR, Reed JC. Mitochondria and apoptosis.Science. 1998;281:1309–1312.PubMedCrossRefGoogle Scholar
  27. 27.
    Liu X, Kim CN, Yang J, Jemmerson, R, Wang X. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c.Cell. 1996;86:147–157.PubMedCrossRefGoogle Scholar
  28. 28.
    Zou H, Henzel WJ, Liu XS, Lutschg A, Wang XD. Apaf-1, a human protein homologous to C-elegans CED-4, participates in cytochrome c-dependent activation of caspase-3.Cell. 1997;90:405–413.PubMedCrossRefGoogle Scholar
  29. 29.
    Koseki T, Inohara N, Chen, S, Nunez G. ARC, an inhibitor of apoptosis expressed in skeletal muscle and heart that interacts selectively with caspases.Proc Natl Acad Sci U S A. 1998;95:5156–5160.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Koseki T, Inohara N, Chen, S, et al. CIPER, a novel NF kappaB-activating protein containing a caspase-recruitment domain with homology to Herpesvirus-2 protein E10.J Biol Chem. 1999;274:9955–9961.PubMedCrossRefGoogle Scholar
  31. 31.
    Johnson DE. Programmed cell death regulation: basic mechanisms and therapeutic opportunities.Leukemia. 2000;14:1340–1344.CrossRefPubMedGoogle Scholar
  32. 32.
    Marchetti P, Castedo M, Susin SA, et al. Mitochondrial permeability transition is a central coordinating event of apoptosis.J Exp Med. 1996;184:1155–1160.PubMedCrossRefGoogle Scholar
  33. 33.
    Skulachev VP. Why are mitochondria involved in apoptosis? Permeability transition pores and apoptosis as selective mechanisms to eliminate superoxide-producing mitochondria and cell.FEBS Lett. 1996;397:7–10.PubMedCrossRefGoogle Scholar
  34. 34.
    Desagher S, Osen-Sand A, Nichols A, et al. Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis.J Cell Biol. 1999;44:891–901.CrossRefGoogle Scholar
  35. 35.
    Shimizu S, Tsujimoto Y. Proapoptotic BH3-only Bcl-2 family members induce cytochrome c release, but not mitochondrial membrane potential loss, and do not directly modulate voltage-dependent anion channel activity.Proc Natl Acad Sci U S A. 2000;97:577–582.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Mancini M, Nicholson DW, Roy S, et al. The caspase-3 precursor has a cytosolic and mitochondrial distribution: implications for apoptotic signaling.J Cell Biol. 1998;140:1485–1495.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Susin SA, Lorenzo HK, Zamzami N, et al. Mitochondrial release of caspase-2 and -9 during the apoptotic process.J Exp Med. 1999;189:381–394.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Susin SA, Lorenzo HK, Zamzami,N, et al. Molecular characterization of mitochondrial apoptosis-inducing factor.Nature. 1999;397:441–446.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Lorenzo HK, Susin SA, Penninger JM, Kroemer G. Apoptosis-inducing factor (AIF): a phylogenetically old, caspase-independent effector of cell death.Cell Death Diff. 1999;6:516–524.CrossRefGoogle Scholar
  40. 40.
    Yang E, Korsmeyer SJ. Molecular thanatopsis: a discourse on the BCL2 family and cell death.Blood. 1996;88:386–401.PubMedGoogle Scholar
  41. 41.
    Reed JC. Bcl-2 and the regulation of programmed cell death.J Cell Biol. 1994;124:1–5.PubMedCrossRefGoogle Scholar
  42. 42.
    Muchmore SW, Sattler M, Liang H, et al. X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death.Nature. 1996;381;335–341.PubMedCrossRefGoogle Scholar
  43. 43.
    Minn AJ, Velez P, Schendel SL, et al. Bcl-x(L) forms an ion channel in synthetic lipid membranes.Nature. 1997;385:353–357.PubMedCrossRefGoogle Scholar
  44. 44.
    Schendel SL, Xie ZH, Montal MO, Matsuyama S, Montal M, Reed JC. Channel formation by antiapoptotic protein Bcl-2.Proc Natl Acad Sci U S A. 1997;94:5113–5118.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Jurgensmeier JM, Xie Z, Devereaux Q, Ellerby L, Bredesden D, Reed JC. Bax directly induces release of cytochrome c from isolated mitochondria.Proc Natl Acad Sci U S A. 1998;95:4997–5002.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death.Cell. 1993;74:609–619.PubMedCrossRefGoogle Scholar
  47. 47.
    Kharbanda S, Pandey P, Schofield L, et al. Role for Bcl-xL as an inhibitor of cytosolic cytochrome C accumulation in DNA damage-induced apoptosis.Proc Natl Acad Sci U S A. 1997;94:6939–6942.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Reed JC. Double identity for proteins of the Bcl-2 family.Nature. 1997;387:773–776.PubMedCrossRefGoogle Scholar
  49. 49.
    Hu Y, Benedict MA, Wu D, Inohara N, Nunez G. Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation.Proc Natl Acad Sci U S A. 1998;95:4386–4391.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Naumovski L, Cleary ML. The p53-binding protein 53BP2 also interacts with Bc12 and impedes cell cycle progression at G2/M.Mol Cell Biol. 1996;16:3884–3892.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Wang HG, Rapp UR, Reed JC. Bcl-2 targets the protein kinase Raf-1 to mitochondria.Cell. 1996;87:629–638.PubMedCrossRefGoogle Scholar
  52. 52.
    Gottlieb RA, Nordberg J, Skowronski E, Babior BM. Apoptosis induced in Jurkat cells by several agents is preceded by intracellular acidification.Proc Natl Acad Sci U S A. 1996;93:654–658.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Matsuyama S, Xu Q, Velours J, Reed JC. The mitochondrial F0F1-ATPase proton pump is required for function of the proapoptotic protein Bax in yeast and mammalian cells.Mol Cell. 1998;1:327–336.PubMedCrossRefGoogle Scholar
  54. 54.
    Sheikh MS, Fornace AJ Jr. Death and decoy receptors and p53-mediated apoptosis.Leukemia. 2000;14:1509–1513.PubMedCrossRefGoogle Scholar
  55. 55.
    MacFarlane M, Ahmad M, Srinivasula SM, Fernandes-Alnemri T, Cohen GM, Alnemri ES. Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL.J Biol Chem. 1997;272:25417–25420.PubMedCrossRefGoogle Scholar
  56. 56.
    Marsters SA, Sheridan JP, Pitti RM, et al. A novel receptor for Apo2L/TRAIL contains a truncated death domain.Curr Biol. 1997;7:1003–1006.PubMedCrossRefGoogle Scholar
  57. 57.
    Schneider P, Bodmer JL, Thome M, Hofmann K, Holler N, Tschopp J. Characterization of two receptors for TRAIL.FEBS Lett. 1997;416:329–334.PubMedCrossRefGoogle Scholar
  58. 58.
    Sheridan JP, Marsters SA, Pitti RM, et al. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors.Science. 1997;277:818–821.PubMedCrossRefGoogle Scholar
  59. 59.
    Emery JG, McDonnell P, Burke MB, et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL.J Biol Chem. 1998;273:14363–14367.PubMedCrossRefGoogle Scholar
  60. 60.
    Pitti RM, Marsters SA, Lawrence DA, et al. Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer.Nature. 1998;396:699–703.PubMedCrossRefGoogle Scholar
  61. 61.
    Sato T, Irie S, Kitada S, Reed JC. FAP-1: a protein tyrosine phosphatase that associates with Fas.Science. 1995;268:411–415.PubMedCrossRefGoogle Scholar
  62. 62.
    Condorelli G, Vigliotta G, Cafieri A, et al. PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis.Oncogene. 1999;18:4409–4415.PubMedCrossRefGoogle Scholar
  63. 63.
    Irmler M, Thome M, Hahne M, et al. Inhibition of death receptor signals by cellular FLIP.Nature. 1997;388:190–195.PubMedCrossRefGoogle Scholar
  64. 64.
    Srinivasula SM, Ahmad M, Ottilie S, et al. FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis.J Biol Chem. 1997;272:18542–18545.PubMedCrossRefGoogle Scholar
  65. 65.
    Jiang Y, Woronicz JD, Liu W, Goeddel DV. Prevention of constitutive TNF receptor 1 signaling by silencer of death domains.Science. 1999;283:543–546.PubMedCrossRefGoogle Scholar
  66. 66.
    Duckett CS, Nava VE, Gedrich RW, et al. A conserved family of cellular genes related to the baculovirus iap gene and encoding apoptosis inhibitors.EMBO J. 1996;15:2685–2694.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Liston P, Roy N, Tamai K, et al. Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes.Nature. 1996:379;349–353.PubMedCrossRefGoogle Scholar
  68. 68.
    Uren AG, Pakusch M, Hawkins CJ, Puls KL, Vaux DL. Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and/or bind tumor necrosis factor receptor-associated factors.Proc Natl Acad Sci U S A. 1996;93:4974–4978.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Seol DW, Billiar TR. A caspase-9 variant missing the catalytic siteis an endogenous inhibitor of apoptosis.J Biol Chem. 1999;274:2072–2076.PubMedCrossRefGoogle Scholar
  70. 70.
    Srinivasula SM, Ahmad M, Guo Y, et al. Identification of an endogenous dominant-negative short isoform of caspase-9 that can regulate apoptosis.Cancer Res. 1999;59:999–1002.PubMedGoogle Scholar
  71. 71.
    Clark DM, Lampert IA. Apoptosis is a common histopathological finding in myelodysplasia: the correlate of ineffective haemato-poiesis.Leuk Lymphoma. 1990;2:415–418.PubMedCrossRefGoogle Scholar
  72. 72.
    Hatfill SJ, Fester ED, Steytler JG. Apoptotic megakaryocyte dysplasia in the myelodysplastic syndromes.Hem Pathol. 1992;6:87–93.Google Scholar
  73. 73.
    Bogdanovic AD, Trpinac DP, Jankovic GM, Bumbasirevic VZ, Obradovic M, Colovic MD. Incidence and role of apoptosis in myelodysplastic syndrome: morphological and ultrastructural assessment.Leukemia. 1997;11;656–659.PubMedCrossRefGoogle Scholar
  74. 74.
    Greenberg PL, Ginzton N, Rajapaksa R, Tong CR, Han JH. Apoptosis in myelodysplastic syndrome (MDS) [abstract].Blood. 1994;84:159a.Google Scholar
  75. 75.
    Raza A, Gezer S, Mundle S, et al. Apoptosis in bone marrow biopsy samples involving stromal and hematopoietic cells in 50 patients with myelodysplastic syndromes.Blood. 1995;86:268–2676.PubMedGoogle Scholar
  76. 76.
    Rajapaksa R, Ginzton N, Rott LS, Greenberg PL. Altered onco-protein expression and apoptosis in myelodysplastic syndrome marrow cells.Blood. 1996;88:4275–4287.PubMedGoogle Scholar
  77. 77.
    Kawabata H, Anzai N, Ueda Y, et al. High levels of Ca(2+)-inde-pendent endonuclease activity capable of producing nucleosomal-size DNA fragmentation in non-adherent marrow mononuclear cells from patients with myelodysplastic syndromes and acute myelogenous leukemia.Leukemia. 1996;10:67–73.PubMedGoogle Scholar
  78. 78.
    Hellstrom-Lindberg E, Kanter-Lewensohn L, Ost A. Morphological changes and apoptosis in bone marrow from patients with myelodysplastic syndromes treated with granulocyte-CSF and ery-thropoietin.Leuk Res. 1997;21:415–425.PubMedCrossRefGoogle Scholar
  79. 79.
    Ali A, Mundle SD, Ragasa D, et al. Sequential activation of cas-pase-1 and caspase-3-like proteases during apoptosis in myelodys-plastic syndromes.J Hematother Stem Cell Res. 1999;8:343–856.PubMedCrossRefGoogle Scholar
  80. 80.
    Tsoplou P, Kouraklis-Symeonidis A, Thanopoulou E, Zikos P, Orphanos V, Zoumbos NC. Apoptosis in patients with myelodys-plastic syndromes: differential involvement of marrow cells in “good” versus “poor” prognosis patients and correlation with apoptosis-related genes.Leukemia. 1999;13:1554–1563.PubMedCrossRefGoogle Scholar
  81. 81.
    Kurotaki H, Tsushima Y, Nagai K, Yagihashi S. Apoptosis, bcl-2 expression and p53 accumulation in myelodysplastic syndrome, myelodysplastic-syndrome-derived acute myelogenous leukemia and de novo acute myelogenous leukemia.Acta Haematologica. 2000;102:115–123.PubMedCrossRefGoogle Scholar
  82. 82.
    Anzai N, Kawabata H, Hirama T, et al. Marked apoptosis of human myelomonocytic cell line P39. Significance of cellular differentiation.Leukemia. 1994;8:446–453.PubMedGoogle Scholar
  83. 83.
    Darzynkiewicz Z, Bedner E, Traganos F, Murakami T. Critical aspects in the analysis of apoptosis and necrosis.Human Cell. 1998;11:3–12.PubMedGoogle Scholar
  84. 84.
    Lepelley P, Campergue L, Grardel N, Preudhomme C, Cosson A, Fenaux P. Is apoptosis a massive process in myelodysplastic syndromes?Br J Haematol. 1996;95:368–371.PubMedCrossRefGoogle Scholar
  85. 85.
    Shetty V, Hussaini S, Broady-Robinson L, et al. Intramedullary apoptosis of hematopoietic cells in myelodysplastic syndrome patients can be massive: apoptotic cells recovered from high-density fraction of bone marrow aspirates.Blood. 2000;96:1388–1392.PubMedGoogle Scholar
  86. 86.
    Parker JE, Fishlock KL, Czepulkowski B, Mijovic A, Pagliuca A, Mufti GJ. “Low risk” myelodysplastic syndrome (MDS) is associated with excessive apoptosis and an increased ratio of proversus anti-apoptotic Bcl-2 related proteins.Br J Haematol. 1998;103:1075–1082.PubMedCrossRefGoogle Scholar
  87. 87.
    Greenberg PL. Apoptosis and its role in the myelodysplastic syndromes: implications for disease natural history and treatment.Leuk Res. 1998;22:1123–1136.PubMedCrossRefGoogle Scholar
  88. 88.
    Parker JE, Mufti GJ, Rasool F, Mijovic A, Devereux S, Pagliuca A. The role of apoptosis, proliferation and the Bcl-2 related proteins in the myelodysplastic syndromes (MDS) and acute myeloid leukaemia secondary to MDS (MDS-AML).Blood. 2000;96:3932–3938.PubMedGoogle Scholar
  89. 89.
    Clark BR, Gallagher JT, Dexter TM. Cell adhesion in the stromal regulation of haemopoiesis.Baillieres Clin Haem. 1992;5:619–652.CrossRefGoogle Scholar
  90. 90.
    Marsh JC, Chang J, Testa NG, Hows JM, Dexter TM. In vitro assessment of marrow “stem cell” and stromal cell function in aplastic anaemia.Br J Haematol. 1991;78:258–267.PubMedCrossRefGoogle Scholar
  91. 91.
    Tuzuner N, Cox C, Rowe JM, Watrous D, Bennett JM. Hypocellular myelodysplastic syndromes (MDS): new proposals.Br J Haematol. 1995;91:612–617.PubMedCrossRefGoogle Scholar
  92. 92.
    Coutinho LH, Geary CG, Chang J, Harrison C, Testa NG. Functional studies of bone marrow haemopoietic and stromal cells in the myelodysplastic syndrome (MDS).Br J Haematol. 1990;75:16–25.PubMedCrossRefGoogle Scholar
  93. 93.
    Silverman LR, Zinzar S, Holland JF. Biological consequences of stromal abnormalities in the myelodysplastic syndrome (MDS): its influence on the hematopoietic dysregulation [abstract].Leuk Res. 1997;21:S20.CrossRefGoogle Scholar
  94. 94.
    Aizawa S, Nakano M, Iwase O, et al. Bone marrow stroma from refractory anemia of myelodysplastic syndrome is defective in its ability to support normal CD34-positive cell proliferation and differentiation in vitro.Leuk Res. 1999;23:239–246.PubMedCrossRefGoogle Scholar
  95. 95.
    Aizawa S, Hiramoto M, Hoshi H, Toyama K, Shima D, Handa H. Establishment of stromal cell line from an MDS RA patient which induced an apoptotic change in hematopoietic and leukemic cells in vitro.Exp Hematol. 2000;28:148–155.PubMedCrossRefGoogle Scholar
  96. 96.
    List AF, Glinsmann-Gibson B, Spier C, Taetle R. In vitro and in vivo response to cyclosporin-A in myelodysplastic syndromes: identification of a hypocellular subset responsive to immune suppression [abstract].Blood. 1992;80:28a.Google Scholar
  97. 97.
    Goossens V, Grooten J, De Vos K, Fiers W. Direct evidence for tumor necrosis factor-induced mitochondrial reactive oxygen intermediates and their involvement in cytotoxicity.Proc Natl Acad Sci U S A. 1995;92:8115–8119.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Peddie CM, Wolf R, McLellan LI, Collins AR, Bowen DT. Oxidative DNA damage in CD34+ myelodysplastic cells is associated with intracellular redox changes and elevated plasma tumour necrosis factor-a concentration.Br J Haematol. 1997;99:625–631.PubMedCrossRefGoogle Scholar
  99. 99.
    Verhoef GE, De Schouwer P, Ceuppens JL, Van Damme J, Goossens W, Boogaerts MA. Measurement of serum cytokine levels in patients with myelodysplastic syndromes.Leukemia. 1992;6:1268–1272.PubMedGoogle Scholar
  100. 100.
    Kitagawa M, Saito I, Kuwata T, et al. Overexpression of tumor necrosis factor (TNF)-a and interferon (IFN)-γ by bone marrow cells from patients with myelodysplastic syndromes.Leukemia. 1997;11:2049–2054.PubMedCrossRefGoogle Scholar
  101. 101.
    Gersuk GM, Beckham C, Loken MR, et al. A role for tumour necrosis factor-a, Fas and Fas-Ligand in marrow failure associated with myelodysplastic syndrome.Br J Haematol. 1998;103:176–188.CrossRefPubMedGoogle Scholar
  102. 102.
    Mundle SD, Reza S, Ali A, et al. Correlation of tumor necrosis factor alpha (TNF alpha) with high Caspase 3-like activity in myelodysplastic syndromes.Cancer Lett. 1999;140:201–207.PubMedCrossRefGoogle Scholar
  103. 103.
    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.PubMedCrossRefGoogle Scholar
  104. 104.
    Musto P, Matera R, Minervini MM, et al. Low serum levels of tumor necrosis factor and interleukin-1 beta in myelodysplastic syndromes responsive to recombinant erythropoietin.Haemato-logica. 1994;79:265–268.Google Scholar
  105. 105.
    Stasi R, Brunetti M, Bussa S, et al. Serum levels of tumour necrosis factor-alpha predict response to recombinant human erythropoietin in patients with myelodysplastic syndrome.Clin Lab Haematol. 1997;19:197–201.PubMedCrossRefGoogle Scholar
  106. 106.
    Shetty V, Mundle S, Alvi S, et al. Measurement of apoptosis, proliferation and three cytokines in 46 patients with myelodysplastic syndromes.Leuk Res. 1996;20:891–900.PubMedCrossRefGoogle Scholar
  107. 107.
    Reza S, Dar S, Andric T, et al. Biologic characteristics of 164 patients with myelodysplastic syndromes.Leuk Lymphoma. 1999;33:281–287.PubMedCrossRefGoogle Scholar
  108. 108.
    Raza A, Qawi H, Lisak L, et al. Patients with myelodysplastic syndromes benefit from palliative therapy with amifostine, pentoxi-fylline, and ciprofloxacin with or without dexamethasone.Blood. 2000;95:1580–1587.PubMedGoogle Scholar
  109. 109.
    Maurer AB, Ganser A, Buhl R, et al. Restoration of impaired cytokine secretion from monocytes of patients with myelodysplastic syndromes after in vivo treatment with GM-CSF or IL-3.Leukemia. 1993;7:1728–1733.PubMedGoogle Scholar
  110. 110.
    Bowen D, Yancik S, Bennett L, Culligan D, Resser K. Serum stem cell factor concentration in patients with myelodysplastic syndromes.Br J Haematol. 1993;85:63–66.PubMedCrossRefGoogle Scholar
  111. 111.
    Visani G, Zauli G, Tosi P, et al. Impairment of GM-CSF production in myelodysplastic syndromes.Br J Haematol. 1993;84:227–231.PubMedCrossRefGoogle Scholar
  112. 112.
    Itoh N, Yonehara S, Ishii A, et al. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis.Cell. 1991;66:233–243.PubMedCrossRefGoogle Scholar
  113. 113.
    Miyawaki T, Uehara T, Nibu R, et al. Differential expression of apoptosis-related Fas antigen on lymphocyte subpopulations in human peripheral blood.J Immunol. 1992;149:3753–3758.PubMedGoogle Scholar
  114. 114.
    Leithauser F, Dhein J, Mechtersheimer G, et al. Constitutive and induced expression of APO-1, a new member of the nerve growth factor/tumor necrosis factor receptor superfamily, in normal and neoplastic cells.Lab Invest. 1993;69:415–429.PubMedGoogle Scholar
  115. 115.
    Liles WC, Kiener PA, Ledbetter JA, Aruffo A, Klebanoff SJ. Differential expression of Fas (CD95) and Fas ligand on normal human phagocytes: implications for the regulation of apoptosis in neutrophils.J Exp Med. 1996;184:429–440.CrossRefPubMedGoogle Scholar
  116. 116.
    Moller P, Henne C, Leithauser F, et al. Coregulation of the APO-1 antigen with intercellular adhesion molecule-1 (CD54) in tonsillar B cells and coordinate expression in follicular center B cells and in follicle center and mediastinal B-cell lymphomas.Blood. 1993;81:2067–2075.PubMedGoogle Scholar
  117. 117.
    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;85:3183–3196.PubMedGoogle Scholar
  118. 118.
    Bellgrau D, Gold D, Selawry H, Moore J, Franzusoff A, Duke RC. A role for CD95 ligand in preventing graft rejection.Nature. 1995;377:630–632.PubMedCrossRefGoogle Scholar
  119. 119.
    Griffith TS, Brunner T, Fletcher SM, Green DR, Ferguson TA. Fas ligand-induced apoptosis as a mechanism of immune privilege.Science. 1995;270:1189–1192.PubMedCrossRefGoogle Scholar
  120. 120.
    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.CrossRefPubMedGoogle Scholar
  121. 121.
    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.PubMedCrossRefGoogle Scholar
  122. 122.
    Lepelley P, Grardel N, Erny O, et al. Fas/APO-1 (CD95) expression in myelodysplastic syndromes.Leuk Lymphoma. 1998;30:307–312.PubMedCrossRefGoogle Scholar
  123. 123.
    Mundle SD, Mativi BY, Bagai K, et al. Spontaneous down-regulation of Fas-associated phosphatase-1 may contribute to excessive apoptosis in myelodysplastic marrows.Int J Hematol. 1999;70:83–90.PubMedGoogle Scholar
  124. 124.
    O’Connell J, O’Sullivan GC, Collins JK, Shanahan F. The Fas counterattack: Fas-mediated T cell killing by colon cancer cells expressing Fas ligand.J Exper Med. 1996;184:1075–1082.CrossRefGoogle Scholar
  125. 125.
    Hahne M, Rimoldi D, Schroter M, et al. Melanoma cell expression of Fas (Apo-1/CD95) ligand: implications for tumor immune escape.Science. 1996;274:1363–1366.PubMedCrossRefGoogle Scholar
  126. 126.
    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.PubMedCrossRefGoogle Scholar
  127. 127.
    Mundle SD, Venugopal P, Cartlidge JD, et al. Indication of an involvement of interleukin-1 beta converting enzyme-like protease in intramedullary apoptotic cell death in the bone marrow of patients with myelodysplastic syndromes.Blood. 1996;88:2640–2647.PubMedGoogle Scholar
  128. 128.
    Campos L, Sabido O, Viallet A, Piselli S, Guyotat D. Implication of ICE and CPP32 in the growth defects of committed progenitors from myelodysplastic syndromes [abstract].Blood. 1997;90:521a.Google Scholar
  129. 129.
    Bouscary D, Chen YL, Guesnu M, et al. Activity of the caspase-3/CPP32 enzyme is increased in “early stage” myelodysplastic syndromes with excessive apoptosis, but caspase inhibition does not enhance colony formation in vitro.Exp Hematol. 2000;28:784–791.PubMedCrossRefGoogle Scholar
  130. 130.
    Boudard D, Sordet O, Vasselon C, et al. Expression and activity of caspases 1 and 3 in myelodysplastic syndromes.Leukemia. 2000;14:2045–2051.PubMedCrossRefGoogle Scholar
  131. 131.
    Delia D, Aiello A, Soligo D, et al. bcl-2 proto-oncogene expression in normal and neoplastic human myeloid cells.Blood. 1992;79;1291–1298.PubMedGoogle Scholar
  132. 132.
    Ter-Harmsel B, Smedts F, Kuijpers J, Jeunink M, Trimbos B, Ramaekers F. BCL-2 immunoreactivity increases with severity of CIN: a study of normal cervical epithelia, CIN, and cervical carcinoma.J Pathol. 1996;179:26–30.PubMedCrossRefGoogle Scholar
  133. 133.
    Krajewska M, Krajewski S, Epstein JI, et al. Immunohistochemical analysis of bcl-2, bax, bcl-x, and mcl-1 expression in prostate cancers.Am J Pathol. 1996;148:1567–1576.PubMedPubMedCentralGoogle Scholar
  134. 134.
    Leiter U, Schmid RM, Kaskel P, Peter RU, Krahn G. Antiapoptotic bcl-2 and bcl-xL in advanced malignant melanoma.Arch Dermatol Research. 2000;292:225–232.CrossRefGoogle Scholar
  135. 135.
    Aguilar-Santelises M, Rottenberg ME, Lewin N, Mellstedt H, Jondal M. Bcl-2, Bax and p53 expression in B-CLL in relation to in vitro survival and clinical progression.Int J Cancer. 1996;69:114–119.PubMedCrossRefGoogle Scholar
  136. 136.
    Pepper C, Hoy T, Bentley DP. Bcl-2/Bax ratios in chronic lymphocytic leukaemia and their correlation with in vitro apoptosis and clinical resistance.Br J Cancer. 1997;76:935–938.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Campos L, Rouault JP, Sabido O, et al. High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy.Blood. 1993;81:3091–3096.PubMedGoogle Scholar
  138. 138.
    Bradbury DA, Zhu YM, Russell NH. Bcl-2 expression in acute myeloblastic leukaemia: relationship with autonomous growth and CD34 antigen expression.Leuk Lymphoma. 1997;24:221–228.PubMedCrossRefGoogle Scholar
  139. 139.
    Davis RE, Greenberg PL. Bcl-2 expression by myeloid precursors in myelodysplastic syndromes: relation to disease progression.Leuk Res. 1998;22:767–767.PubMedCrossRefGoogle Scholar
  140. 140.
    Lepelley P, Soenen V, Preudhomme C, Merlat A, Cosson A, Fenaux P. bcl-2 expression in myelodysplastic syndromes and its correlation with hematological features, p53 mutations and prognosis.Leukemia. 1995;9:726–730.PubMedGoogle Scholar
  141. 141.
    Sherr CJ. Cancer cell cycles.Science. 1996;274:1672–1677.CrossRefPubMedGoogle Scholar
  142. 142.
    Bincoletto C, Saad ST, Soares da Silva E, Queiroz ML. Autonomous proliferation and bcl-2 expression involving haematopoietic cells in patients with myelodysplastic syndrome.Br J Cancer. 1998;78:621–624.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Raza A, Alvi S, Borok RZ, et al. Excessive proliferation matched by excessive apoptosis in myelodysplastic syndromes: the cause-effect relationship.Leuk Lymphoma. 1997;27:111–118.PubMedCrossRefGoogle Scholar
  144. 144.
    Jonveaux P, Fenaux P, Quiquandon I, et al. Mutations in the p53 gene in myelodysplastic syndromes.Oncogene. 1991;6:2243–2247.PubMedPubMedCentralGoogle Scholar
  145. 145.
    Sugimoto K, Hirano N, Toyoshima H, et al. Mutations of the p53 gene in myelodysplastic syndrome (MDS) and MDS-derived leukemia.Blood. 1993;81:3022–3026.PubMedGoogle Scholar
  146. 146.
    Wattel E, Preudhomme C, Hecquet B, et al. p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies.Blood. 1994;84:3148–3157.PubMedGoogle Scholar
  147. 147.
    Uchida T, Kinoshita T, Nagai H, et al. Hypermethylation of the p15INK4B gene in myelodysplastic syndromes.Blood. 1997;90:1403–1409.PubMedGoogle Scholar
  148. 148.
    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. 1998;91:2985–2990.PubMedGoogle Scholar
  149. 149.
    Karsdorf A, Dresch C, Metral J, Najean Y. Prognostic value of the combined suicide level of granulocyte progenitors and the labelling index of precursors in preleukemic states and oligoblastic leukemias.Leuk Res. 1983;7:279–286.PubMedCrossRefGoogle Scholar
  150. 150.
    Montecucco C, Riccardi A, Traversi E, et al. Flow cytometric DNA content in myelodysplastic syndromes.Cytometry. 1983;4:238–243.PubMedCrossRefGoogle Scholar
  151. 151.
    Peters SW, Clark RE, Hoy TG, Jacobs A. DNA content and cell cycle analysis of bone marrow cells in myelodysplastic syndromes (MDS).Br J Haematol. 1986;62:239–245.PubMedCrossRefGoogle Scholar
  152. 152.
    Raza A, Alvi S, Broady-Robinson L, et al. Cell cycle kinetic studies in 68 patients with myelodysplastic syndromes following intravenous iodo- and/or bromodeoxyuridine.Exp Hematol. 1997;25:530–535.PubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2001

Authors and Affiliations

  1. 1.The Department of Haematological MedicineGuy’s, King’s, Thomas’ School of MedicineLondonUK

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