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International Journal of Hematology

, Volume 75, Issue 3, pp 289–297 | Cite as

Biological Significance of Proliferation, Apoptosis, Cytokines, and Monocyte/Macrophage Cells in Bone Marrow Biopsies of 145 Patients With Myelodysplastic Syndrome

  • Krishnan Allampallam
  • Vilasini Shetty
  • Suneel Mundle
  • Diya Dutt
  • Howard Kravitz
  • Poluru L. Reddy
  • Sairah Alvi
  • Naomi Galili
  • Gurveen S. Saberwal
  • Shalini Anthwal
  • Maliha W. Shaikh
  • Aaron York
  • Azra Raza
Case Report

Abstract

Labeling index (LI), apoptosis, levels of 2 pro-apoptotic cytokines tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β), and the number of monocyte/macrophage cells that are the likely source of the cytokines were simultaneously measured in plastic-embedded bone marrow (BM) biopsy sections of 145 patients with myelodysplastic syndromes (MDS). TNF-α was correlated with TGF-β (P = .001) and with monocyte/macrophage cells (P = .003). Patients with excess blasts in their marrows had a higher TGF-β level (P = .01) and monocyte/macrophage number (P = .05). In a linear regression model, TGF-β emerged as the most significant biological difference between patients who have excess of blasts and those who do not (P = .01). We conclude that in addition to TNF-α, TGF-β also plays a significant role in the initiation and pathogenesis of MDS, and that a more precise definition of its role will likely identify better preventive and therapeutic strategies.

Key words

Myelodysplastic syndromes Cytokines Labeling index Apoptosis Tumor necrosis factor-α Transforming growth factor-β Monocyte/macrophage cells 

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References

  1. 1.
    Iverson PO. Blood flow to the hematopoietic bone marrow.Acta Physiol Scand. 1997;159:269–276.CrossRefGoogle Scholar
  2. 2.
    Wickramasinghe SN.Blood and Bone Marrow. 3rd ed. London, England: Churchill Livingstone; 1986.Google Scholar
  3. 3.
    San Miguel JF, Sanz GF, Vellaspi T, Canizo MC, Sanz MA. Myelodysplastic syndromes.Crit Rev Oncol Hematol. 1996;23:57–93.CrossRefPubMedGoogle Scholar
  4. 4.
    Resegotti L. The nature and natural history of myelodysplasia.Haematologica. 1993;5:191–204.Google Scholar
  5. 5.
    Raza A, Gezer S, Mundle S, Gao XZ, et al. Apoptosis in bone marrow biopsy samples involving stromal and hematopoietic cells in 50 patients with myelodysplastic syndromes.Blood. 1995;86:268–276.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Raza A, Gregory SA, Preisler HD. The myelodysplastic syndromes in 1996: complex stem cell disorders confounded by dual actions of cytokines.Leuk Res. 1996;20:881–890.CrossRefPubMedGoogle Scholar
  7. 7.
    Molnar L, Berki T, Hussain A, et al. Detection of TNF alpha expression in the bone marrow and determination of TNF alpha production of peripheral blood mononuclear cells in myelodysplastic syndrome.Pathol Oncol Res. 2000;6:18–23.CrossRefPubMedGoogle Scholar
  8. 8.
    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.CrossRefPubMedGoogle Scholar
  9. 9.
    Mundle SD, Venugopal P, Pandav DV, et al. Indication of an involvement of interleukin-1β converting enzyme (ICE)-like protease in intramedullary apoptotic cell death in the bone marrows of patients with myelodysplastic syndromes (MDS).Blood. 1996;88:2640–2647.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Allampallam K, Shetty V, Hussaini S, et al. Measurement of mRNA expression for a variety of cytokines and its receptors in bone marrows of patients with myelodysplastic syndromes.Anticancer Res. 1999;19:5323–5328.PubMedGoogle Scholar
  11. 11.
    Peddie CM, Wolf CR, 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-β concentration.Br J Haematol. 1997;99:625–631.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Zoumbos N, Symeonidis A, Kourakli A, et al. Increased levels of soluble interleukin-2 receptors and tumor necrosis factor in serum of patients with myelodysplastic syndromes.Blood. 1991;77:413–414.PubMedGoogle Scholar
  13. 13.
    Herold M, Schmalzl F, Zwierzina H. Increased serum interleukin 6 levels in patients with myelodysplastic syndromes.Leuk Res. 1992;16:585–588.CrossRefPubMedGoogle Scholar
  14. 14.
    Mareni C, Sessarego M, Montera M, et al. Expression and genomic configuration of GM-CSF, IL-3 M-CSF receptor (C-FMS), early growth response gene-1 (EGR-1) and M-CSF genes in primary myelodysplastic syndromes.Leuk Lymphoma. 1994;15:135–141.CrossRefGoogle Scholar
  15. 15.
    Gersuk GM, Beckham C, Loken MR, et al. A role for tumour necrosis factor-β, FAS and FAS-Ligand in marrow failure associated with myelodysplastic syndrome.Br J Haematol. 1998;103:176–188.CrossRefGoogle Scholar
  16. 16.
    Kitagawa M, Yamaguchi S, Takahashi M, Tanizawa T, Hirokawa K, Kamiyama R. Localization of Fas and Fas ligand in bone marrow cells demonstrating myelodysplasia.Leukemia. 1998;12:486–492.CrossRefGoogle Scholar
  17. 17.
    Mundle S, Mativi BY, Bagai K, et al. Spontaneous down-regulation of Fas-associated phosphatase-1 (Fap-1) may contribute to the excessive apoptosis in myelodysplastic marrows.Int J Hematol. 1999;70:83–90.Google Scholar
  18. 18.
    Raza A, Venugopal P, Gezer S, et al. Pilot study of pentoxifylline and Ciprofloxacin with or without dexamethasone produces encouraging results in myelodysplastic syndromes. In: Hiddemann W, Buchner T, Wormann B, Ritter J, Creutzig U, Keating M, Plunkett W, eds.Acute Leukemias VII: Experimental Approaches and Novel Therapies. New York, NY: Springer-Verlag; 1998:42–51.CrossRefGoogle Scholar
  19. 19.
    Raza A, Qawi H, Andric T, et al. Pentoxifylline, Ciprofloxacin and dexamethasone improve the ineffective hematopoiesis in myelodysplastic syndrome patients.Hematology. 2000;5:275–284.CrossRefGoogle Scholar
  20. 20.
    Raza A. Anti-TNF therapies in rheumatoid arthritis, Crohn’s disease, sepsis, and myelodysplastic syndromes.Microsc Res Tech. 2000;50:229–235.CrossRefPubMedGoogle Scholar
  21. 21.
    Bennett JM, Catovsky D, Flandrin DMT, Galton DGAD, Gralnick HR, Sultan C. Proposal for the classification of myelodysplastic syndromes.Br J Haematol. 1982;51:189–199.CrossRefGoogle Scholar
  22. 22.
    Greenberg PL, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes.Blood. 1997;89:2079–2088.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Raza A, Alvi S, Broady-Robinson L, et al. Cell cycle kinetic studies in 68 patients with myelodysplastic syndromes following intravenous iodo- and/or bromodeoxyuride.Exp Hematol. 1997;25:530–535.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Raza A, Yousuf N, Bokhari SAJ, et al. Cell cycle characteristics: alterable determinants of remission duration in a study of 179 standard risk newly diagnosed patients with acute myeloid leukemia.Int J Oncol. 1993;2:301–307.PubMedGoogle Scholar
  25. 25.
    Raza A, Mundle S, Iftikhar A, et al. Simultaneous assessment of cell kinetics and programmed cell death in bone marrow biopsies of myelodysplastics reveals extensive apoptosis as the probable basis for ineffective hematopoiesis.Am J Hematol. 1995;48:143–154.CrossRefPubMedGoogle Scholar
  26. 26.
    Raza A, Mundle S, Shetty V, et al. A paradigm shift in myelodysplastic syndromes.Leukemia. 1996;10:1648–1652.PubMedGoogle Scholar
  27. 27.
    Rajapaksa R, Ginzton N, Rott LS, Greenberg PL. Altered oncoprotein expression and apoptosis in myelodysplastic syndrome marrow cells.Blood. 1996;88:4275–4287.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Parcharidou A, Raza A, Economopoulos T, et al. Extensive apoptosis of bone marrow cells as evaluated by the in-situ end labeling (ISEL) technique may be the basis for ineffective hematopoiesis in patients with myelodysplastic syndromes.Eur J Haematol. 1999;62:19–26.CrossRefPubMedGoogle Scholar
  29. 29.
    Shimazaki K, Ohshima K, Suzumiya J, Kawasaki C, Kijuchi M. Evaluation of apoptosis as a prognostic factor in myelodysplastic syndromes.Br J Hematol. 2000;110:584–590.CrossRefGoogle Scholar
  30. 30.
    Van de Loosdrecht AA, Vellenga E. Myelodysplasia and apoptosis: new insights into ineffective erythropoiesis.Med Oncol. 2000;17:16–21.CrossRefPubMedGoogle Scholar
  31. 31.
    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 and acute myeloid leukemia secondary to MDS.Blood. 2000;96:3932–3938.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Shetty V, Hussaini S, Broady-Robinson L, Allampallam K, 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.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Alvi S, Borok R, Showel M, et al. Formation of large molecular weight DNA fragments may be a committed step of apoptosis in myelodysplastic syndromes vs acute myeloid leukemia [abstract].Proc Am Assoc Cancer Res. 1996;37:Abstract 185.Google Scholar
  34. 34.
    Papadaki HA, Giouremou K, Eliopoulos GD. Low frequency of myeloid progenitor cells in chronic idiopathic neutropenia of adults may be related to increased production of TGF-β by bone marrow stromal cells.Eur J Haematol. 1999;63:154–162.CrossRefGoogle Scholar
  35. 35.
    Vindevoghel L, Lechleider RJ, Kon A, et al. SMADk3/4-dependent transcriptional activation of the human type VII collagen gene (COL7A1) promoter by transforming growth factor β.Proc Natl Acad Sci U S A. 1998;95:14769–14774.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Dar S, Mundle S, Andric T, et al. Biological characteristics of myelodysplastic syndrome patients who demonstrated high versus no intramedullary apoptosis.Eur J Haematol. 1999;62:90–94.CrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2002

Authors and Affiliations

  • Krishnan Allampallam
    • 1
  • Vilasini Shetty
    • 1
  • Suneel Mundle
    • 1
  • Diya Dutt
    • 1
  • Howard Kravitz
    • 1
  • Poluru L. Reddy
    • 1
  • Sairah Alvi
    • 1
  • Naomi Galili
    • 1
  • Gurveen S. Saberwal
    • 1
  • Shalini Anthwal
    • 1
  • Maliha W. Shaikh
    • 1
  • Aaron York
    • 1
  • Azra Raza
    • 1
  1. 1.Rush Cancer Institute, Rush-Presbyterian-St. Luke’s Medical CenterChicago, IllinoisUSA

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