Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Manuscript
  • Published:

Myeloysplasias

Involvement of transforming growth factor-β and thrombopoietin in the pathogenesis of myelodysplastic syndrome with myelofibrosis

Abstract

We investigated the cause of myelofibrosis and proliferation of megakaryocytes in myelodysplastic syndrome with myelofibrosis (MDS-MF (+)). Plasma-transforming growth factor-β1 (PTGF-β1) concentrations closely correlated with myelofibrosis grade in MDS-MF (+) and were higher than those in idiopathic myelofibrosis (IMF), essential thrombocythemia (ET), idiopathic thrombocytopenic purpura (ITP), MDS-without MF (MDS-MF (−)) or healthy volunteers (HV). Peripheral blood mononuclear cells from MDS-MF (+) patients expressed more TGF-β1 mRNA than those from IMF, MDS-MF (−) or HV. When we immunostained bone marrow specimens of MDS-MF (+) for TGF-β, the intensity of blasts was apparently higher than that of megakaryocytes, while in MDS-MF (−), megakaryocytes were immunostained with a similar intensity as that in MDS-MF (+), but blasts were negative for staining. In IMF, megakaryocytes, monocytes and small mononuclear cells representing CD34+ cells were all similarly stained with a much lower intensity than that of blasts in MDS-MF (+). The number of bone marrow megakaryocytes were increased the most in MDS-MF (+), followed by ET, ITP, MDS-MF (−) and NHL and correlated with plasma thrombopoietin (TPO) levels or with plasma TGF-β1 levels, respectively, in each disease. Thus, in MDS-MF (+), both myelofibrosis and the increased megakaryocytes were ascribed to overproduction of TGF-β1 from blasts.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Ohyashiki K, Sasao I, Ohyashiki JH, Murakami T, Tauchi T, Iwabuchi A et al. Cytogenetic and clinical findings of myelodysplastic syndromes with a poor prognosis. An experience with 97 cases. Cancer 1992; 70: 94–99.

    Article  CAS  PubMed  Google Scholar 

  2. Kampmeier P, Anastasi J, Vardiman JW . Issues in the pathology of the myelodysplastic syndromes. Hematol Oncol Clin North Am 1992; 6: 501–522.

    Article  CAS  PubMed  Google Scholar 

  3. Maschek H, Georgii A, Kaloutsi V, Werner M, Bandecar K, Kressel MG et al. Myelofibrosis in primary myelodysplastic syndromes: a retrospective study of 352 patients. Eur J Haematol 1992; 48: 208–214.

    Article  CAS  PubMed  Google Scholar 

  4. Verhoef GE, De Wolf-Peeters C, Ferrant A, Deprez S, Meeus P, Stul M et al. Myelodysplastic syndromes with bone marrow fibrosis: a myelodysplastic disorder with proliferative features. Ann Hematol 1992; 63: 235–241.

    Article  Google Scholar 

  5. Lambertenghi-Deliliers G, Annaloro C, Oriani A, Soligo D, Pozzoli E, Polli EE . Prognostic relevance of histological findings on bone marrow biopsy in myelodysplastic syndromes. Ann Hematol 1993; 66: 85–91.

    Article  CAS  PubMed  Google Scholar 

  6. Yoshida Y, Stephenson J, Mufti GJ . Myelodysplastic syndromes: from morphology to molecular biology. Part I. Classification, natural history and cell biology of myelodysplasia. Int J Hematol 1993; 57: 87–97.

    CAS  PubMed  Google Scholar 

  7. Imbert M, Nguyen D, Sultan C . Myelodysplastic syndrome (MDS) and acute myeloid leukemias (AML) with myelofibrosis. Leuk Res 1992; 16: 51–54.

    Article  CAS  PubMed  Google Scholar 

  8. Sultan C, Sigaux F, Imbert M, Reyes F . Acute myelodysplasia with myelofibrosis: a report of eight cases. Br J Haematol 1981; 49: 11–16.

    Article  CAS  PubMed  Google Scholar 

  9. Lambertenghi-Deliliers G, Orazi A, Luksch R, Annaloro C, Soligo D . Myelodysplastic syndrome with increased marrow fibrosis: a distinct clinicopathological entity. Br J Haematol 1991; 78: 161–166.

    Article  CAS  PubMed  Google Scholar 

  10. Le Bousse-Kerdiles MC, Chevillard S, Charpentier A, Romquin N, Clay D, Smadja-Joffe F et al. Differential expression of transforming growth factor-beta, basic fibroblast growth factor, and their receptors in CD34+ hematopoietic progenitor cells from patients with myelofibrosis and myeloid metaplasia. Blood 1996; 88: 4534–4546.

    CAS  PubMed  Google Scholar 

  11. Rameshwar P, Chang VT, Thacker UF, Gascon P . Systemic transforming growth factor-beta in patients with bone marrow fibrosis – pathophysiological implications. Am J Hematol 1998; 59: 133–142.

    Article  CAS  PubMed  Google Scholar 

  12. Martyre MC, Romquin N, Le Bousse-Kerdiles MC, Chevillard S, Benyahia B, Dupriez B et al. Transforming growth factor-beta and megakaryocytes in the pathogenesis of idiopathic myelofibrosis. Br J Haematol 1994; 88: 9–16.

    Article  CAS  PubMed  Google Scholar 

  13. Terui T, Niitsu Y, Mahara K, Fujisaki Y, Urushizaki Y, Mogi Y et al. The production of transforming growth factor-beta in acute megakaryoblastic leukemia and its possible implications in myelofibrosis. Blood 1990; 75: 1540–1548.

    CAS  PubMed  Google Scholar 

  14. Thiele J, Kvasnicka HM, Beelen DW, Flucke U, Spoer C, Paperno S et al. Megakaryopoiesis and myelofibrosis in chronic myeloid leukemia after allogenic bone marrow transplantation: an immunohistochemical study of 127 patients. Mod Pathol 2000; 12: 129–138.

    Google Scholar 

  15. Martyre MC . TGF-beta and megakaryocytes in the pathogenesis of myelofibrosis in myeloproliferative disorders. Leuk Lymphoma 1995; 20: 39–44.

    Article  CAS  PubMed  Google Scholar 

  16. Martyre MC, Le Bousse-Kerdiles MC, Romquin N, Chevillard S, Praloran V, Demory JL et al. Elevated levels of basic fibroblast growth factor in megakaryocytes and platelets from patients with idiopathic myelofibrosis. Br J Haematol 1997; 97: 441–448.

    Article  CAS  PubMed  Google Scholar 

  17. Hirayama Y, Sakamaki S, Matsunaga T, Kuga T, Kuroda H, Kusakabe T et al. Concentrations of thrombopoietin in bone marrow in normal subjects and in patients with idiopathic thrombocytopenic purpura, aplastic anemia, and essential thrombocythemia correlate with its mRNA expression of bone marrow stromal cells. Blood 1998; 92: 4652.

    Google Scholar 

  18. Kuroda H, Matsunaga T, Terui T, Tanaka I, Takimoto R, Fujikawa K et al. Decrease of Smad4 gene expression in patients with essential thrombocythaemia may cause an escape from suppression of megakaryopoiesis by transforming growth factor-beta1. Br J Haematol 2004; 124: 211–220.

    Article  CAS  PubMed  Google Scholar 

  19. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982; 51: 189–199.

    Article  CAS  PubMed  Google Scholar 

  20. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR et al. Proposal for the recognition of minimally differentiated acute myeloid leukaemia (AML-MO). Br J Haematol 1991; 78: 325–329.

    Article  CAS  PubMed  Google Scholar 

  21. Manoharan A, Horsley R, Pitney WR . The reticulin content of bone marrow in acute leukaemia in adults. Br J Haematol 1989; 43: 185–190.

    Article  Google Scholar 

  22. Sakamaki S, Hirayama Y, Matsunaga T, Kuroda H, Kusakabe T, Akiyama T et al. Transforming growth factor-beta1 (TGF-beta1) induces thrombopoietin from bone marrow stromal cells, which stimulates the expression of TGF-beta receptor on megakaryocytes and, in turn, renders them susceptible to suppression by TGF-beta itself with high specificity. Blood 1999; 94: 1961–1970.

    CAS  PubMed  Google Scholar 

  23. Miyanishi K, Takayama T, Ohi M, Hayashi T, Nobuoka A, Nakajima T et al. Glutathione S-transferase-pi overexpression is closely associated with K-ras mutation during human colon carcinogenesis. Gastroenterology 2001; 121: 865–874.

    Article  CAS  PubMed  Google Scholar 

  24. Hisai H, Kato J, Kobune M, Murakami T, Miyanishi K, Takahashi M et al. Increased expression of angiogenin in hepatocellular carcinoma in correlation with tumor vascularity. Clin Cancer Res 2003; 9: 4852–4859.

    CAS  PubMed  Google Scholar 

  25. Cordel JL, Falini B, Erber WN, Ghosh AK, Abdulaziz Z, Mac Donald S et al. Immunoenzymatic labeling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase. J Histochem Cytochem 1984; 32: 219–229.

    Article  Google Scholar 

  26. Ogura M, Morishima Y, Ohno R, Kato Y, Hirabayashi N, Nagura H et al. Establishment of a novel human megakaryoblastic leukemia cell line, MEG-01, with positive Philadelphia chromosome. Blood 1985; 66: 1384–1392.

    CAS  PubMed  Google Scholar 

  27. Battinelli E, Willoughby SR, Foxall T, Valeri CR, Loscalzo J . Induction of platelet formation from megakaryocytoid cells by nitric oxide. Proc Natl Acad Sci USA 2001; 98: 14458–14463.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89: 2079–2088.

    CAS  PubMed  Google Scholar 

  29. Wang JC, Chen C, Lou LH, Mora M . Blood thrombopoietin, IL-6 and IL-11 levels in patients with agnogenic myeloid metaplasia. Leukemia 1997; 11: 1827–1832.

    Article  CAS  PubMed  Google Scholar 

  30. Yan XQ, Lacey D, Hill D, Chen Y, Fletcher F, Hawley RG et al. A model of myelofibrosis and osteosclerosis in mice induced by overexpressing thrombopoietin (mpl ligand): reversal of disease by bone marrow transplantation. Blood 1996; 88: 402–409.

    CAS  PubMed  Google Scholar 

  31. Kuter DJ, Rosenberg RD . The reciprocal relationship of thrombopoietin (c-Mpl ligand) to changes in the platelet mass during busulfan-induced thrombocytopenia in the rabbit. Blood 1995; 85: 2720–2730.

    CAS  PubMed  Google Scholar 

  32. Takabayashi M, Sakai R, Kanamori H, Ishigatsubo Y . Successful treatment with intermediate dose cytosine arabinoside for myelodysplastic syndrome with acute myelofibrosis. Leuk Lymphoma 2003; 44: 891–892.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Mr Kevin Litton (Bachelor of arts in English) for editorial assistance.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to T Matsunaga.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Akiyama, T., Matsunaga, T., Terui, T. et al. Involvement of transforming growth factor-β and thrombopoietin in the pathogenesis of myelodysplastic syndrome with myelofibrosis. Leukemia 19, 1558–1566 (2005). https://doi.org/10.1038/sj.leu.2403875

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403875

Keywords

This article is cited by

Search

Quick links