Biology of Stem and Myeloid Progenitor Cells in Myelodysplastic Syndromes

  • Lambert F. R. Span
  • Theo M. de Witte
Part of the Cancer Treatment and Research book series (CTAR, volume 108)


The myelodysplastic syndromes (MDS) are hyperproliferative, acquired clonal stem cell disorders, associated with massive intramedullary apoptosis or programmed cell death (PCD). A leukemic phenotype, mainly characterized by an increase of blasts showing differentiation arrest, is gradually observed, as MDS progresses from low-risk (LR-MDS) to high-risk MDS (HR-MDS). Three interacting compartments can be distinguished in MDS, the polyclonal, residual normal hematopoiesis, the monoclonal preleukemic compartment, and the blastic leukemic compaitnient. Within LRMDS, monoclonal hematopoiesis dominates leukemic blast cell proliferation (<5%), whereas this pattern is reversing during MDS evolution to acute myeloid leukemia (AML). This shift in the balance of proliferation versus apoptosis has to be applied constantly to these three interacting compartments in MDS. For illustration, the following example and nomenclature is used. Stem Cell Factor (SCF) is a major factor to induce differentiation and to mediate the transition from the earliest CD34 negative (CD34−) stem cells to the more differentiated CD34 positive (CD34+) stem cells, whereas IL-6 promotes proliferation and maintains self-renewal of CD34+ stem cells. The balance and interaction between these cytokines may play different roles in normal, monoclonal, and leukemic hematopoiesis(“static profile” of these compartments).


Acute Myeloid Leukemia Myelodysplastic Syndrome Stem Cell Factor FasL Expression Leukemic Clone 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aizawa, S., Nakano, M., Iwase, O., Yaguchi, M., Hiramoto, M., Hoshi, H., Nabeshima, R., Shima, D., Handa, H., Toyama, K. (1999) Bone marrow stroma from refractory anemia of myelodysplastic syndrome is defective in its ability to support normal CD34 positive cell proliferation and differentiation.Leukemia Research23, 239–246.PubMedCrossRefGoogle Scholar
  2. Bogdanovic, A.D., Tripnac, D.P., Jankovic, G.M., Bumbasirevic, V.Z., Obradovic, M., Colovic, M.D. (1997) Incidence and role of apoptosis in myelodysplastic syndrome: morphological and ultrastructural assessment.Leukemia 11656–659.PubMedCrossRefGoogle Scholar
  3. Bouscary, D., De Vos, J., Guesnu, M., Jondeau, K., Viguier, F., Melle, J., Picard, F., Dreyfus, F., Fontenay-Roupie, M. (1997) Fas/APO-1 (CD95) expression and apoptosis in patients with myelodysplastic syndromes.Leukemia 11839–845.PubMedCrossRefGoogle Scholar
  4. Bouscary, D., Chen, Y.L., Guesnu, M., Picard, F., Viguier, F., Lacombe, C., Dreyfus, F., Fontenay-Roupie, M. (2000) 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.Experimental Hematology28, 784–791.PubMedCrossRefGoogle Scholar
  5. Cheng, J., Zhou T., Liu, C., Shapiro, J.P., Brauer, M.J. Kiefer, M.C., Barr, P.J., Mountz J.D. (1994) Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule.Science263, 1759–1762.PubMedCrossRefGoogle Scholar
  6. Deeg, H.J., Beckham, C., Loken, M.R., Bryant, E., Lesnikova, M., Shulman H.M., Gooley, T. (2000) Negative regulators of hematopoicsis and stroma function in patients with myelodysplastic syndrome.Leukemia Lymphoma37, 405–414.PubMedGoogle Scholar
  7. Degliantoni, G., Perussia, B., Mangoni, L., Trinchieri G. (1985) Inhibition of bone marrow colony formation by human natural killer cells and by natural killer cell-derived colony-inhibiting activity.Journal of Experimental Medicine 161, 1152–1168. PubMedCrossRefGoogle Scholar
  8. Flores-Figueroa, E., Gutierrez-Espindola, G., Guerrero-Rivera, S., Pizzuto-Chavez, J., Mayani H. (1999) Hematopoietic progenitor cells from patients with myelodysplastic syndromes: in vitro colony growth and long-term proliferation.Leukemia Research 23385–394.PubMedCrossRefGoogle Scholar
  9. Gerritsen, W.R., Donohue, J., Bauman, J., etal (1992) Clonal analysis of myelodysplastic syndrome: monosomy 7 is expressed in the myeloid lineage, but not in the lymphoid lineage as detected by fluorescent in situ hybridization.Blood 80217–224.PubMedGoogle Scholar
  10. Gersuk, G.M., Beckham, C., Loken M.R., Kiener, P., Anderson J.E., Farrand, A., Troutt, A.B., Ledbetter, J.A., Deeg H.J. (1998) A role for tumour necrosis factor-a, Fas and Fas-Ligand in marrow failure associated with myelodysplastic syndrome.British Journal of Hematology 103176–188.CrossRefGoogle Scholar
  11. Greenberg, P.L. (1983) The smoldering myeloid leukemic states: clinical and biological features.Blood 611035–1044.PubMedGoogle Scholar
  12. Greenberg, P., Cox, C., LeBeau, M.M., Fenaux, P., Morel, P., Sanz, G., Sanz, M., Vallespi, T., Hamblin, T., Oscier, D., Ohyashiki, K., Toyama, K., Aul, C., Mufti, G., Bennett, J. (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes.Blood 892079–2088.PubMedGoogle Scholar
  13. Gupta, P., Niehans, G.A., LeRoy, S.C., Gupta, K., Morrison, V.A., Knapp, D., Kratzke, R.A. (1999) Fas ligand expression in the bone marrow in myelodysplastic syndromes correlates with FAB subtype and anemia, and predicts survival.Leukemia 1344–53.PubMedCrossRefGoogle Scholar
  14. Guyotat, D., Campos, L., Thomas, X., Vila, I., Shi, Z.-H., Charrin, C., Gentilhomme, O., Fiere, D. (1990) Myelodysplastic syndromes: A study of surface markers and in vitro growth patterns.American Journal of Hematology34, 26–31.PubMedCrossRefGoogle Scholar
  15. Hellstrom-lindberg, E., Kanter-Lewensohn, L., Ost, A. (1997) Morphological changes and apoptosis in bone marrow from patients with myelodysplastic syndromes treated with G-CSF and erythropoitin.Leukemia Research 21415–425.PubMedCrossRefGoogle Scholar
  16. Horikawa, K., Nakakuma, H., Kawaguchi, T., Iwamoto, N., Nagakura, S., Kagimoto, T., Takatsuki, K. (1997) Apoptosis resistance of blood cells from patients with paroxysmal nocturnal hemoglobinuria, aplastic anemia and myelodysplastic syndrome.Blood 902716–2722.PubMedGoogle Scholar
  17. Josefsen, D., Myklebust, J.H., Lynch, D.H., Stokke, T., Blomhoff, H.K., Smeland, E.B.(1999)Fas ligand promotes cell survival of immature human bone marrow CD34+CD38hcmatopoietic progenitor cells by suppressing apoptosis.Experimental Hematology 271451–1459.PubMedCrossRefGoogle Scholar
  18. Kayagaki, N., Kawasaki, A., Ebata, T., Ohmoto, H., Ikeda, S., Inoue, S., Yoshino, K., Okumura, K., Yagita, H. (1995) Metalloproteinase-mediated release of human Fas ligand.Journal of Experimental Medicine 182 1777–1783. PubMedCrossRefGoogle Scholar
  19. Kerndrup, G., Bendix-Hansen, K., Pedersen, B., Ellegaard, J., Hokland, P. (1988) Analysis of leukocyte differentiation antigens in blood and bone marrow in patients with refractory anaemia (RA) and RA with sideroblasts. Prognostic indications of sequential and follow-up data.European Journal of Haematology 41368–374.PubMedCrossRefGoogle Scholar
  20. Kibbelaar, R.E., van Kamp, H., Dreef, E.J. et al (1992) Combined immunophenotyping and DNA in situ hybridization to study lineage involvement in patients with myelodysplastic syndromes.Blood 79, 1823–1828. PubMedGoogle Scholar
  21. Kiener, P.A., Davis, P.M., Starling, G.C., Mehlin, C., Klebanoff S.J., Ledbetter, J.A., Liles, W.C. (1997) Differential induction of apoptosis by Fas-Fas ligand interactions in human monocytes and macrophages.Journal of Experimental Medicine 1851511–1516.PubMedCrossRefGoogle Scholar
  22. Kitagawa, M., Saito, I., Kuwata, T., Yoshida, S., Yamaguchi S., Takahashi, M., Tanizawa, T., Kamiyama, R., Hirokawa, K. (1997) Overexpression of tumor necrosis factor (TNF)alpha and interferon (IFN)-gamma by bone marrow cells from patients with myelodysplastic syndromes.Leukemia 112049–2054.PubMedCrossRefGoogle Scholar
  23. Kitagawa, M., Yamaguchi, S., Takahashi, M., Tanizawa, T., Hirokawa, K., Kamiyama, R. (1998) Localization of Fas and Fas ligand in bone marrow cells demonstrating myelodysplasia.Leukemia 12486–492.PubMedCrossRefGoogle Scholar
  24. Knipping, E., Debatin, K-M., Stricker, K., Heilig, B., Eder, A., Krammer, P.H. (1995) Identification of a soluble APO-1 in supematants of human B- and T-cell lines and increased serum levels in B- and T-cell leukemias.Blood 851562–1569.PubMedGoogle Scholar
  25. Kristensen, J.S. & Hokland, P. (1990) Monoclonal antibody ratios in malignant myeloid diseases: diagnostic and prognostic use in myelodysplastic syndromes.British Journal of Haematology 74270–276.PubMedCrossRefGoogle Scholar
  26. Kroef, M.J., Fibbe, W.E., Mout, R., Jansen, R.P., Haak, H.L., Wessels, J.W. Van Kamp, H., Willemze, R., Landegent, J.E. (1993) Myeloid but not lymphoid cells carry the 5q deletion: polymerase chain reaction analysis of loss of heterozygosity using mini-repeat sequences on highly purified cell fractions. Blood 811849–1854.PubMedGoogle Scholar
  27. Lepelley, P., Campergue, L., Grardel, N., Preudhomme, C., Cosson, A., Fenaux, P. (1996) Is apoptosis a massive process in myelodysplastic syndromes?British Journal of Haematology 95368–371.PubMedCrossRefGoogle Scholar
  28. van Lom, K., Hagemeijer, A., Vandekerckhove, F., Smit, E.M.E., Lowenberg, B. (1996) Cytogenetic clonality analysis: typical patterns in myelodysplastic syndrome and acute meyloid leukemia.Britisch Journal of Haematology 93594–600.CrossRefGoogle Scholar
  29. Maciejewski, J., Selleri, C., Anderson, S., Young, N.S. (1995) 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 853183–3190.PubMedGoogle Scholar
  30. Mayani, H., Baines, P., Bowen, D.T., Jacobs, A. (1989) In vitro growth of myeloid and erythroid progenitor cells from myelodysplastic patients in response to recombinanthuman granulocyte-macrophage colony-stimulating factor.Leukemia 329–32.PubMedGoogle Scholar
  31. Mehrotra, B., George T.I., Kavanau, K., Avet-Loiseau, H., MooreII. D.,Willman, C.L., Slovak, M.L., Atwater, S., Head, D.R., Pallavicini, M.G. (1995) Cytogenetically aberrant cells in the stem cell compartment (CD34+lin—) in acute myeloid leukemia.Blood 861139–1147.PubMedGoogle Scholar
  32. Merchav, S., Wagemarker, G., Souza, L.M., Tatarsky, I. (1991) Impaired response of myelodysplastic marrow progenitors to stimulation with recombinant hematopoietic growth factors.Leukemia 5340–346.PubMedGoogle Scholar
  33. Mundle, S., lftikhar, A., Shetty, V., Dameron, S., Wright-Quinones, V., Marcus, B., Loew, J., Gregory, S., Raza, A. (1994) Novel in situ double labeling for simultaneous detection of proliferation and apoptosis.Journal of histochemistry and Cytochemistry 421533–1537.PubMedCrossRefGoogle Scholar
  34. Mundle, S.D., Ali, A., Cartlidge, J.D., Reza, S., Alvi, S., Showel, M.M., Mativi, B.Y., Shetty, V.T., Venugopal, P., Gregory, S.A., Raza, A. (1999a) Evidence for involvement of tumor necrosis factor-alpha in apoptotic death of bone marrow cells in myelodysplastic syndromes.American Journal of Hematology 6036–47.CrossRefGoogle Scholar
  35. Mundle, S., Venugopal, P., Shetty, V., Ali, A., Chopra, H., Handa, H., Rose, S., Mativi, B.Y., Gregory, S.A., Preisler, H.D., Raza, A. (1999b) The relative extent and propensity of CD34+ vs. CD34— cells to undergo apoptosis in myelodysplastic marrows.International Journal of Hematology 69152–159.Google Scholar
  36. Mundle, S.D., Mativi, B.Y., Bagai, K., Feldman, G., Cheema, P., Gautam, U., Reza, S., Cartlidge, J.D., Venugopal, P., Shetty, V., Gregory, S.A., Robin, E., Rifkin, S., Shah, R., Raza, A. (1999c) Spontaneous down-regulation of Fas-associated phosphatase- I may contribute to excessive apoptosis in myelodysplastic marrows.International Journal of Hematology 7083–90.Google Scholar
  37. Nagafuji, K., Shibuya, T., Harada, M., Mizuno, S.I., Takenaka, K., Miyamoto, T., Okamura, T., Gondo, H., Niho, Y. (1995) Functional expression of Fas antigen (CD95) on hematopoietic progenitor cells.Blood86, 883–889.PubMedGoogle Scholar
  38. Nagata, S. (1997) Apoptosis by death factor.Cell88, 355–356.PubMedCrossRefGoogle Scholar
  39. Nagata, S. & Golstein, P. (1995) The Fas death factor.Science267, 1449–1456.PubMedCrossRefGoogle Scholar
  40. Nagler, A., MacKichan, M.L., Negrin, R.S., Donlon, T., Greenberg, G.L. (1995) Effects of granulocyte colony-stimulating factor therapy on in vitro hemopoiesis in myelodysplastic syndromes.Leukemia9, 30–39.PubMedGoogle Scholar
  41. NihoY. &Asano, Y. (1998) Fas/Fas ligand and hematopoietic progenitor cells.Current Opinion in Hematology5, 163–165.PubMedCrossRefGoogle Scholar
  42. Nilsson, L., Xstrand-Grundstr m, I., Arvidsson, I., Jacobsson, B., Hellstr m-Lindberg, E., Hast, R., Jacobsen, S.E.W. (2000) Isolation and characterization of hematopoietic progenitor/stem cells in 5q—deleted myelodysplastic syndromes: evidence for involvement at the hematopoietic stem cell level.Blood96, 2012–2021.PubMedGoogle Scholar
  43. Novitzky, N., Mohamed, R., Finlayson, J., du Toit, C. (2000) Increased apoptosis of bone marrow cells and preserved proliferative capacity of selected progenitors predict for clinical response to anti-inflammatory therapy in myelodysplastic syndromes.Experimental Hematology28, 941–949.PubMedCrossRefGoogle Scholar
  44. Pantel, K. & Nakeff, A (1993) The role of lymphoid cells in hematopoietic regulation.Experimental Hematology21, 738–742.PubMedGoogle Scholar
  45. Parker, J.E., Mufti, G.J., Rasool, F., Mijovic, A., Devereux, S., Pagliuca, A. (2000) The role of apoptosis, proliferation, and the BcI-2-related proteins in the myelodysplastic syndromes and acute myeloid leukemia secondary to MDS.Blood96, 3932–3938.PubMedGoogle Scholar
  46. Pcderson-Bjergaard, J. & Rowley J.D. (1994) The balanced and the unbalanced chromosome aberrations of acute myeloid leukemia may develop in different ways and may contribute differently to malignant transformation.Blood83, 2780–2786.Google Scholar
  47. Pederson-Bjergaard, J., Pedersen, M., Roulston, D., Philip, P. (1995) Different genetic pathways in leukemogenesis for patients presenting with therapy-related myelodysplasia and therapy-related acute myeloid leukemia.Blood86, 3542–3552.Google Scholar
  48. Rajapaksa, R., Ginzton, N., Rott, L.S., Greenberg, P.L. (1996) Altered oncoprotein expression and apoptosis in myelodysplastic syndrome marrow cells.Blood88, 4275–4287.PubMedGoogle Scholar
  49. Raymakers, R., de Witte, T., Joziasse, J., van der Lely, N., Boezeman, J. and Haanen, C. (1991) In vitro growth pattern and differentiation predict for progression of myelodysplastic syndromes to acute nonlymphocytic leukaemia.British Journal of Haematology78, 35–41.PubMedCrossRefGoogle Scholar
  50. Raza, A., Gezer, S., Mundle, S., Gao, X.-Z., Alvi, S., Borok, R., Rifkin, S., Iftikhar, A., Shetty, V., Parcharidou, A., Loew, J., Marcus, B., Khan, Z., Chaney, C., Showel, J., Gregory, S., Preisler, H. (1995) Apoptosis in bone marrow biopsy samples involving stromal and hematopoietic cells in 50 patients with myelodysplastic syndromes.Blood86, 268–276.PubMedGoogle Scholar
  51. Raza, A., Mundle, S., Shetty, V., Alvi, S., Chopra, H., Span, L., Parcharidou, A., Dar, S., Venugopal, P., Borok, R., Gezer, S., Showel, J., Loew, J., Robin, E., Rifkin, S., Alston, D., Hernandez, B., Shar, R., Kaizer, H., Gregory, S. (1996) Novel insights into the biology of myelodysplastic syndromes: excessive apoptosis and the role of cytokines.International Journal of Hematology63, 265–278.PubMedCrossRefGoogle Scholar
  52. Raza, A., Alvi, S., Borok, R.Z., Span, L., Parcharidou, A., Alston, D., Rifkin, S., Robin, E., Shah, R., Gregory, S.A. (1997) Excessive proliferation matched by excessive apoptosis in myelodysplastic syndromes: the cause-effect relationship.Leukemia and Lymphoma27, 111–118.PubMedGoogle Scholar
  53. Raza, A., Qawi, H., Lisak, L., Andric, T., Dar, S., Andrews, C., Venugopal, P., Gezer, S., Gregory, S., Loew, J., Robin, E., Rifkin, S., Hsu, W.T., Huang, R.W. (2000) Patients with myelodysplastic syndromes benefit from palliative therapy with amifostine, pentoxifylline, and ciprofloxacin with or without dexamethasone.Blood95, 1580–1587.PubMedGoogle Scholar
  54. Reza, S., Shetty, V., Dar, S., Qawi, H., Raza, A. (1998) Tumor necrosis factor-alpha levels decrease with anticytokine therapy in patients with myelodysplastic syndromes.Journal of Interferon and Cytokine Research18, 871–877.PubMedCrossRefGoogle Scholar
  55. Sato, T., Irie, S., Kitada, S.&Reed, J.C. (1995) FAP-l: a protein tyrosine phosphatase that associates with Fas.Science268, 411–415.PubMedCrossRefGoogle Scholar
  56. Sato, T., Kim, S., Seller’, C., Young, N.S., Maciejewski, J.P. (1998) Measurement of secondary colony formation after 5 weeks in long-term cultures in patients with myelodysplastic syndrome.Leukemia12, 1187–1194.PubMedCrossRefGoogle Scholar
  57. Sawada, K.-I. (1994) Impaired proliferation and differentiation of myelodysplastic CD34+ cells.Leukemia and Lymphoma14, 37–47.PubMedCrossRefGoogle Scholar
  58. Sawada, K., Sato, N., Notoya, A., Tarumi, T., Hirayama, S., Takano, H., Koizumi, K., Yasukouchi, T., Yamaguchi, M., Koike, T. (1995) Proliferation and differentiation of myelodysplastic CD34+ cells: Phenotypic subpopulations of marrow CD34+ cells.Blood85, 194–202.PubMedGoogle Scholar
  59. Sawada, K., Ieko, M., Notoya, A., Tarumi, T., Koizumi, K., Kitayama, S., Nishio, H., Fukada, Y., Yasukouchi, T., Yamaguchi, M., Katoh, S., Koike, T. (1996) Role of cytokines in leukemic type growth of myelodysplastic CD34+ cells.Blood88, 319–327.PubMedGoogle Scholar
  60. Sawada K.-I., Koizumi, K., Tarumi, T., Takano, H., leko, M., Nishio, M., Fukada, Y., Yasukouchi, T., Yamaguchi, M., Koike, T. (1999) Role of physiological concentrations of stem cell factor in leukemic type growth of myelodysplastic CD34+ cells.Leukemia Research23, 1–11.PubMedCrossRefGoogle Scholar
  61. Schulze-Osthoff, K. (1994) The Fas/APO-1 receptor and its deadly ligand.Trends in Cell Biology4, 421–426.PubMedCrossRefGoogle Scholar
  62. Seller’, C., Sato, T., Raiola, A.M., Rotoli, B., Young, N.S., Maciejewski, J.P. (1997) Induction of nitric oxide synthase is involved in the machanism of Fas-mediated apoptosis in haematopoietic cells.British Journal of Haematology99, 481–489.CrossRefGoogle Scholar
  63. Shetty, V., Mundle, S., Alvi, S., Showel, M., Broady-Robinson, L., Dar, S., Borok, R., Showel, J., Gregory, S., Gezer, S., Venugopal, P., Shah, R., Hernandez, B., Klein, M., Robin, E., Dominguez, C., Raza, A. (1996) Measurement of apoptosis, proliferation and three cytokines in 46 patients with myelodysplastic syndromes.Leukemia Research20, 891–900.PubMedCrossRefGoogle Scholar
  64. Shetty, V., Hussaini, S., Broady-Robinson, L., Allampallam, K., Mundle, S., Borok, R., Broderick, E., Mazzoran, L., Zorat, F., Raza, A. (2000) Intramedullary apoptosis of hematopoietic cells in myelodysplastic syndrome patients can be massive: apoptotic cells recovered from high-density fraction of bone marrow aspirates.Blood96, 1388–1392.PubMedGoogle Scholar
  65. Sloand, E.M., Young, N.S., Sato, T., Kim, S., Maciejewski, J.P. (1998) Inhibition of interleukin-lbeta-converting enzyme in human hematopoietic progenitor cells results in blockade of cytokine-mediated apoptosis and expansion of their proliferative potential.Experimental Hematology26, 1093–1099.PubMedGoogle Scholar
  66. Soligo, D.A., Campiglio, S., Servida, F., Bossolasco, P., Romitti, L., Cortelezzi, A., Lambertenghi Deliliers, D. (1996) Response of myelodysplastic syndrome marrow progenitor cells to stimulation with cytokine combinations in a stroma-free long-term culture system.British Journal of Haematology92, 548–558.PubMedCrossRefGoogle Scholar
  67. Span, L.F.R., Dar, S.E., Shetty, V., Mundle, S.D., Broady-Robinson, L., Alvi, S., Raymakers, R.A.P., de Witte, T., Raza, A. (1998a) Apparent expansion of CD34+ cells during the evolution of myelodysplastic syndromes to acute myeloid leukemia.Leukemia12,1685–1695.CrossRefGoogle Scholar
  68. Span, L.F.R., Raymakers, R.A.P., Rutten, E.S.M., de Witte, Th. (1998b) Proliferation and apoptosis characteristics in vitro in myelodysplasia, AML, and normal bone marrow. (Abstract).British Journal of Haematology102, P-1358.Google Scholar
  69. Span, L.F., Vierwinden, G., Pennings, A.H., Boezeman, J.B., Raymakers, R.A., de Witte, T.J. (1999) Programmed cell death of CD34+ cells in MDS is clearly enhanced in cluster forming cells but remarkably decreased in colony forming cells. (Abstract).Blood94, Suppl. 1, #467.Google Scholar
  70. Stahnke, K., Hecker, S., Kohne, E., Debatin K-M (1998) CD95 (APO-l/FAS)-mediated apoptosis in cytokine-activated hematopoietic cells.Experimental Hematology26, 844–850.PubMedGoogle Scholar
  71. Suda, T., Hashimoto, H., Tanaka, M., Ochi, T., Nagata, S. (1997) Membrane Fas Ligand kills human peripheral blood T lymphocytes and soluble Fas Ligand blocks the killing.Journal of Experimental Medicine86, 2045–2050.CrossRefGoogle Scholar
  72. Sullivan, S.A., Marsden, K.A., Lowenthal, R.M., Jupe, D.M., Jones, M.E. (1992) Circulating CD34+ cells: an adverse prognostic factor in myelodysplastic syndromes.American Journal of Hematology39, 96–101.PubMedCrossRefGoogle Scholar
  73. Tamura, S., Kanamaru, A., Kakishita, E., Nagai, K. (1992) Detection of latent subclones with abnormal karyotypes by long-term bone marrow cultures in cases of myelodysplastic syndrome.British Journal of Haematology81, 353–361.PubMedCrossRefGoogle Scholar
  74. Tanaka, M., Suda, T., Takahashi, T., Nagata, S. (1995) Expression of the functional soluble form of human Fas Ligand in activated lymphocytes. European. Mol. Biol. Organ. 14 1129–1135. Google Scholar
  75. Tanaka, M., Itai, T., Adachi, M., Nagata, S. (1998) Downregulation of Fas ligand by shedding.Nature Medicine4, 31–36.PubMedCrossRefGoogle Scholar
  76. Tohyama, K., Ueda, T., Yoshida Y., Nakamura, T. (1994) Altered responses of purified blast cells from the myelodysplastic syndromes to colony-stimulating factors in vitro: Comparison with normal blast cells.Experimental Hematology22, 539–545.PubMedGoogle Scholar
  77. Verma, D.S., Spitzer, G., Dicke, K.A., McCredie, K.B. (1979) In vitro agar culture pattems in preleukemia and their clinical significance.Leukemia Research3, 41–49.PubMedCrossRefGoogle Scholar
  78. Villunger, A., Egle, A., Marschitz, I., Kos, M., Bock, G., Ludwig, H., Geley, S., Kofler, R., Greil, R. (1997) Constitutive expression of fas (APO-1/CD95) ligand on multiple myeloma cells: a potential mechanism of tumor-induced suppression of immune surveillance.Blood90, 12–20.PubMedGoogle Scholar
  79. Wallach, D., Boldin, M., Goncharov, T., Goltsev, Y., Mett, I., Malinin, N., Adar, R., Kovalenko, A., Varfolomeev, E. (1996) Exploring cell death mechanisms by analyzing signaling cascades of the TNF/NGF receptor family.Behring Inst Mitt97, 144–155.PubMedGoogle Scholar
  80. Yoshida, Y. (1993) Hypothesis: apoptosis may be the mechanism responsible for the premature intramedullary cell death in the myelodysplastic syndrome.Leukemia7, 144–146.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Lambert F. R. Span
    • 1
  • Theo M. de Witte
    • 1
  1. 1.Department of HematologyUniversity Medical Center NijmegenNijmegenThe Netherlands

Personalised recommendations