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Functional disturbance of marrow stromal microenvironment in the myelodysplastic syndromes

Leukemia volume 16, pages 785–790 (2002)Cite this article

Abstract

The potential contribution of abnormal marrow stromal function to ineffective haemopoiesis in the myelodysplastic syndromes is unclear. We have compared the ability of stromal layers from normal (n = 7) and myelodysplastic (n = 9) marrow to alter proliferation and survival of the granulocyte–macrophage colony-stimulating factor/interleukin-3-dependent cell line F-36P. Co-cultures for 72 h in the absence of exogenous cytokines were either in direct contact with stroma or separated by transwell inserts. On normal stromal layers, the ratio of adherent F-36P cells relative to stromal cells increased from a mean of 0.2 ± 0.01 (s.d.) at 4 h of co-culture to 0.34 ± 0.08 after 72 h (n = 7). Corresponding values on myelodysplastic stroma (0.2 ± 0.02 at 4 h and 0.35 ± 0.05 at 72 h; n = 9) indicated that the ability of myelodysplastic stromal layers to regulate short-term proliferation of F-36P cells may be similar to normal. Apoptosis of F-36P cells was quantified after co-culture with normal or myelodysplastic stroma: results from myelodysplastic co-cultures were standardized as a fraction of values from co-cultures with paired normal stroma (apoptotic ratio). Augmented apoptosis of F-36P cells was detected in 8/9 co-cultures with myelodysplastic stroma (mean = 15.7 ± 9.7%, n = 9), compared with corresponding normal stroma (mean = 12.4 ± 4.6%, n = 7, P < 0.05) with a mean apoptotic ratio of 1.4 ± 0.5 (P < 0.05). There was no correlation between stroma-related apoptosis and FAB type, tumour necrosis factor-α concentrations in the culture supernatant or numbers of stromal macrophages, and no evidence of involvement of the Fas pathway. Increased apoptosis was detected in cells grown in transwell inserts over stroma (23.8 ± 3%, n = 5) compared to adherent cells in cultures with normal stromal layers, but this survival difference was not observed in co-cultures with myelodysplastic stroma. These results suggest that abnormal stromal function in patients with myelodysplastic syndromes may contribute to increased apoptosis of haemopoietic cells within the marrow microenvironment. The effect appears to be dependent on close cellular contact, rather than the release of soluble factors, but the exact mechanism remains unclear.

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References

  1. Raza A, Gezer S, Mundle S, Gao X, 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 . Apoptosis in bone marrow biopsy samples involving stromal and hematopoietic cells in 50 patients with myelodysplastic syndromes Blood 1995 86: 268–276

    CAS  PubMed  Google Scholar 

  2. Rajapaksa R, Ginzton N, Rott LS, Greenberg PL . Altered oncoprotein expression and apoptosis in myelodysplastic syndrome marrow cells Blood 1996 88: 4275–4287

    CAS  PubMed  Google Scholar 

  3. Mangi MH, Newland AC, Mufti GJ . Regulatory role of hematopoietic growth factors in abnormal localization of immature precursors (ALIP) formation in myelodysplastic syndrome Blood 1996 88: 376 (Abstr.)

    Google Scholar 

  4. Shetty V, Mundle S, Alvi S, Showel M, Broady-Robinson L, Dar S, Borok R, Showel J, Gregory S, Rifkin S, Gezer S, Parcharidou A, Venugopal P, Shah R, Hernandez B, Klein M, Alston D, Robin E, Dominquez C, Raza A . Measurement of apoptosis, proliferation and three cytokines in 46 patients with myelodysplastic syndromes Leuk Res 1996 20: 891–900

    Article  CAS  Google Scholar 

  5. 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

    Article  CAS  Google Scholar 

  6. Tennant GB, Walsh V, Truran LN, Edwards P, Mills KI, Burnett AK . Reduced growth of normal myeloid progenitors on MDS stroma is unrelated to confluence Br J Haematol 2000 111: 853–862

    CAS  PubMed  Google Scholar 

  7. Aizawa S, Nakano M, Iwase O, Yaguchi M, Hiramoto M, Hoshi H, Nabeshima R, Shima D, Handa H, Toyama K . 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

    Article  CAS  Google Scholar 

  8. Chiba S, Takaku F, Tange T, Shibuya K, Misawa C, Sasaki K, Miyagawa K, Yazaki Y, Hirai H . Establishment and erythroid differentiation of a cytokine-dependent human leukemic cell line F-36: a parental line requiring granulocyte–macrophage colony-stimulating factor or interleukin-3, and a subline requiring erythropoietin Blood 1991 78: 2261–2268

    CAS  PubMed  Google Scholar 

  9. de Wynter E, Allen T, Coutinho L, Flavell D, Flavell SU, Dexter TM . Localisation of granulocyte macrophage colony-stimulating factor in human long-term bone marrow cultures. Biological and immunocytochemical characterisation J Cell Sci 1991 106: 761–769

    Google Scholar 

  10. Gibson FM, Scopes J, Daly S, Rizzo S, Ball SE, Gordon-Smith EC . Interleukin-3 is produced by normal stroma in long-term bone marrow cultures Br J Haematol 1995 90: 518–525

    Article  CAS  Google Scholar 

  11. Moreau I, Andreoni C, Caux C, Saeland S, Rigal D . Modification of human long-term bone marrow cultures: establishment of a functional stromal microenvironment devoid of myeloid progenitors Eur J Haematol 1992 49: 29–35

    Article  CAS  Google Scholar 

  12. Martin SJ, Lennon SV, Bonham AM, Cotter TG . Induction of apoptosis (programmed cell death) in human leukemic HL-60 cells by inhibition of RNA or protein synthesis J Immunol 1990 6: 1859–1867

    Google Scholar 

  13. Philpott NJ, Scopes J, Marsh JC, Gordon-Smith EC, Gibson FM . Increased apoptosis in aplastic anemia bone marrow progenitor cells: possible pathophysiologic significance Exp Hematol 1995 23: 1642–1648

    CAS  PubMed  Google Scholar 

  14. 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 haemopoietic and leukaemic cells in vitro Exp Hematol 2000 28: 148–155

    Article  CAS  Google Scholar 

  15. van de Loosdrecht AA, Ossenkoppele GJ, Beelen RHJ, Broekhoven MG, Drager AM, Langenhuijsen MMAC . Apoptosis in tumor necrosis factor-α dependent monocyte mediated leukemic cell death. A functional, morphological and flowcytometric analysis Exp Hematol 1993 21: 1628–1639

    CAS  PubMed  Google Scholar 

  16. van de Loosdrecht AA, Beelen RH, Ossenkoppele GJ, Broekhoven MG, Langenhuijsen MM . Cellular and cytokine dependent monocyte-mediated leukemic cell death: modulation by interferon-gamma and tumor necrosis factor-alpha Exp Hematol 1993 21: 461–468

    CAS  PubMed  Google Scholar 

Download references

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Author notes

  1. CM Peddie

    Present address: School of Biomedical Sciences, University of St Andrews, St Andrews, Scotland, UK

Authors and Affiliations

  1. Department of Molecular and Cellular Pathology, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, UK

    S Tauro, MD Hepburn, CM Peddie, DT Bowen & MJ Pippard

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The Editor of this manuscript T de Witte generated a short debate that is presented in the Correspondence section of this issue

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Tauro, S., Hepburn, M., Peddie, C. et al. Functional disturbance of marrow stromal microenvironment in the myelodysplastic syndromes. Leukemia 16, 785–790 (2002). https://doi.org/10.1038/sj.leu.2402440

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