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Cited by 238Myeloproliferative Neoplasms: Diagnosis and TreatmentTGF-β signaling in diseasesPlatelet Disorders and Treatments

Prominent role of TGF-β1 in thrombopoietin-induced myelofibrosis in mice

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Chagraoui, Hédia, Komura, Emiko, Tulliez, Micheline, Giraudier, Stéphane, Vainchenker, William, Wendling, Françoise·2002·Blood
DOI 10.1182/blood-2002-04-1133
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Abstract

Several studies suggest an implication of transforming growth factor-β1 (TGF-β1) in the promotion of myelofibrosis associated with hematopoietic malignancies, but the involvement of this cytokine is not fully investigated. To test directly the impact of TGF-β1 in the pathogenesis of myelofibrosis, bone marrow stem cells from homozygous TGF-β1 null (TGF-β1−/−) and wild-type (WT) littermates were infected with a retrovirus encoding the murine thrombopoietin (TPO) protein and engrafted into lethally irradiated wild-type hosts for long-term reconstitution. Over the 4 months of follow-up, TPO levels in plasma were markedly elevated in both groups of mice, and animals typically developed a myeloproliferative syndrome characterized by thrombocytosis, leukocytosis, splenomegaly, increased numbers of progenitors in blood, and extramedullary hematopoiesis. Severe fibrosis was observed in spleen and marrow from all the mice engrafted with WT cells. In contrast, none of the mice repopulated with TGF-β1−/− cells (chimerism > 70%) showed deposition of reticulin fibers at any time during the follow-up. In accordance with the development of fibrosis, latent TGF-β1 levels in plasma and extracellular fluid of the spleen from mice engrafted with WT cells were increased 6-fold and 4-fold, respectively, over levels found in normal hosts, whereas no increase over baseline levels could be demonstrated in animals undergoing transplantation with TGF-β1−/− cells. These data provide evidence that TGF-β1 produced by hematopoietic cells is pivotal for the pathogenesis of myelofibrosis that develops in mice with TPO overexpression.

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  • CD9 and VWF are closely associated with MkP differentiation.

    “In the MkPs, we identified a downregulation of CD9 and VWF , closely associated with MkP differentiation 46-49 , upon IFNa treatment ( Supplementary Fig. 4b ) which is consistent with the decrease in the proportion of MkP observed after IFNa treatment.”

    From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [49]

    The Marrow cell preparation and infection section describes progenitor-cell enrichment, and the Pathological changes in tissues section describes megakaryocyte proliferation, but neither links CD9 or VWF to MkP differentiation. Searches for CD9, VWF, and megakaryocytic differentiation found no passage addressing that link; page numbers were unavailable in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • In MkPs, CD9 and VWF were downregulated upon IFNa treatment.

    “In the MkPs, we identified a downregulation of CD9 and VWF , closely associated with MkP differentiation 46-49 , upon IFNa treatment ( Supplementary Fig. 4b ) which is consistent with the decrease in the proportion of MkP observed after IFNa treatment.”

    From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [49]

    The cited paper’s Marrow cell preparation and infection and Discussion passages concern thrombopoietin-transduced mouse cells and TGF-β1, not IFNa treatment of MkPs. Searches for CD9, VWF, and interferon-alpha found no passage addressing their downregulation. The citing sentence points to its own Supplementary Fig. 4b for that observation. (LLM, conf=0.76)

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Research works printed but not linked: 43

  1. Anderson J, Appelbaum F. Myelodysplasia and myeloproliferative disorders. Curr Opin Hematol. 1997;4:261-267.
  2. Reilly J. Pathogenesis and management of idio- pathic myelofibrosis. Baillieres Clin Haematol. 1998;4:751-767.
  3. Barosi G. Myelofibrosis with myeloid metaplasia: diagnostic definition and prognostic classification for clinical studies and treatment guidelines. J Clin Oncol. 1999;17:2954-2970.
  4. Jacobson R, Salo A, Fialkow P. Agnogenic my- eloid metaplasia: a clonal proliferation of hemato- poietic stem cells with secondary myelofibrosis. Blood. 1978;51:189-194.
  5. Greenberg B, Woo L, Veomett I, Payne CM, Ah- mann F. Cytogenetics of bone marrow fibroblastic cells in idiopathic chronic myelofibrosis. Br J Haematol. 1987;66:487-490.
  6. Thiele J, Hoeppner B, Zankovich R, Fischer R. Histomorphometry of bone marrow biopsies in primary osteomyelofibrosis/sclerosis (agnogenic myeloid metaplasia): correlations between clinical and morphological features. Anat Histopathol. 1989;415:191-199.
  7. Martyre M. TGF-␤ and megakaryocytes in the pathogenesis of myelofibrosis in myeloprolifera- tive disorders. Leuk Lymphoma. 1995;20:39-44.
  8. Martyre M, Le Bousse-Kerdiles MC, Romquin N, et al. Elevated levels of basic fibroblast growth factor in megakaryocytes and platelets from pa- tients with idiopathic myelofibrosis. Br J Haema- tol. 1997;97:441-448.
  9. Rameshwar P, Chang V, Thacker U, Gascon P. Systemic transforming growth factor-␤ in patients with bone marrow fibrosis: pathophysiological implications. Am J Hematol. 1998;59:133-142.
  10. Le Bousse-Kerdiles MC, Martyre M. Dual implica- tion of fibrogenic cytokines in the pathogenesis of fibrosis and myeloproliferation in myeloid meta- plasia with myelofibrosis. Ann Hematol. 1999;78: 437-444.
  11. Roberts A, Sporn M, Assoian R, et al. Transform- ing growth factor type ␤: rapid induction of fibrosis and angiogenesis in vivo and stimulation of colla- gen formation in vitro. Proc Natl Acad Sci U S A. 1986;83:4167-4171.
  12. Kimura A, Kotoh O, Hyodo H, Kuramoto A. Trans- forming growth factor-␤ regulates growth as well as collagen and fibronectin synthesis of human marrow fibroblasts. Br J Haematol. 1989;72:489- 491.
  13. Massague ´J. The transforming growth factor-␤ family. Annu Rev Cell Biol. 1990;6:597-641.
  14. Ignotz R, Endo T, Massagne ´J. Regulation of fi- bronectin and type I collagen mRNA levels by transforming growth factor-␤. J Biol Chem. 1987; 262:6443-6446.
  15. Mervin J, Anderson J, Kocher O, van Itallie C, Madri J. Transforming growth factor-␤ modulates extracellular matrix organisation and cell-cell junctional complex formation during in vitro angio- genesis. J Cell Physiol. 1990;142:117-128.
  16. Castro-Malaspina H. Pathogenesis of myelofibro- sis: role of ineffective megakaryopoiesis and megakaryocyte components. Prog Clin Biol Res. 1984;154:427-454.
  17. Terui T, Niitsu J, Mahara K, et al. The production of transforming growth factor-␤ in acute megakaryoblastic leukemia and its possible impli- cations in myelofibrosis. Blood. 1990;75:1540- 1548.
  18. Reilly J, Barnett D, Dolan G, Forrest P, Eastmam J, Smith A. Characterization of an acute micro- megakaryocytic leukemia: evidence for the pathogenesis of myelofibrosis. Br J Haematol. 1993;83:58-62.
  19. Ulich TR, Del Castillo J, Senaldi G, et al. Sys- temic hematologic effects of PEG-rHuMGDF- induced megakaryocyte hyperplasia in mice. Blood. 1996;87:5006-5015.
  20. Yanagida M, Ide Y, Toriyama M, et al. The role of transforming growth factor-␤ in PEG-rHuMGDF- induced reversible myelofibrosis in rats. Br J Haematol. 1997;99:739-745.
  21. Yan X-Q, Lacey D, Flechter F, et al. Chronic ex- posure to retroviral vector encoded MGDF (mpl- ligand) induces lineage-specific growth and differ- entiation of megakaryocytes in mice. Blood. 1995;86:4025-4033.
  22. Yan X-Q, Lacey D, Hill D, et al. A model of myelo- fibrosis and osteosclerosis in mice induced by overexpressing thrombopoietin (mpl ligand): re- versal of disease by bone marrow transplanta- tion. Blood. 1996;88:402-409.
  23. Villeval JL, Cohen-Solal K, Tulliez M, et al. High thrombopoietin production by hemopoietic cells induces a fatal myeloproliferative syndrome in mice. Blood. 1997;90:4369-4383.
  24. Shull M, Ormsby I, Kier A, et al. Targeted disrup- tion of the mouse transforming growth factor-␤1 gene results in multifocal inflammatory disease. Nature. 1992;359:693-699.
  25. Kallapur S, Ormsby I, Doetschman T. Strain de- pendency of TGF-␤1 function during embryogen- esis. Mol Reprod Dev. 1999;52:341-349.
  26. Pear W, Miller J, Xu L, et al. Efficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receiving P210 bcr/abl-transduced bone marrow. Blood. 1998;92: 3780-3792.
  27. Keller J, McNiece I, Sill K, et al. Transforming growth factor ␤ directly regulates primitive murine hematopoietic cell proliferation. Blood. 1990;75: 596-602.
  28. Sitnicka E, Ruscetti F, Priestley G, Wolf N, Bartel- mez S. Transforming growth factor ␤1 directly and reversibly inhibits the initial cell divisions of long term repopulating hematopoietic stem cells. Blood. 1996;88:82-88.
  29. Ishibashi T, Miller S, Burstein S. Type ␤ trans- forming growth factor is a potent inhibitor of megakaryocytopoiesis in vitro. Blood. 1987;69: 1737-1741.
  30. Kuter D, Gminski D, Rosenberg R. Transforming growth factor ␤ inhibits megakaryocytic growth and endomitosis. Blood. 1992;79:619-626.
  31. Keller J, Jacobson S, Sill K, Elligsworth L, Rusc- etti F. Stimulation of granulopoiesis by transform- ing growth factor ␤: synergy with granulocyte/ macrophage-colony stimulating factor. Proc Natl Acad Sci U S A. 1991;88:7190-7194.
  32. Border W, Noble N. Transforming growth factor ␤ in tissue fibrosis. N Engl J Med. 1994;331:1286- 1292.
  33. Kulkarni AB, Huh CG, Becker D, et al. Transform- ing growth factor-␤ 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci U S A. 1993;90:770- 774.
  34. Yan X, Brady G, Iscove N. Overexpression of PDGF-B in murine hematopoietic cells induces a lethal myeloproliferative syndrome in vivo. Onco- gene. 1994;9:163-173.
  35. Bonyadi M, Rusholme S, Cousins F, et al. Map- ping of a major genetic modifier of embryonic le- thality in TGF␤1 knockout mice. Nat Genet. 1997; 15:207-211.
  36. Yaswen L, Kulkarni A, Frederickson T, et al. Auto- immune manifestations in the transforming growth factor-␤1 knockout mouse. Blood. 1996; 87:1439-1445.
  37. Burns J, Friedmann T, Driever W, Burrascano M, Yee J. Vesicular stomatitis virus G glycoprotein pseudotyped retroviral vectors: concentration to very high titer and efficient gene transfer into mammalian and nonmammalian cells. Proc Natl Acad Sci U S A. 1993;90:8033-8037.
  38. Rebel V, Tanaka M, Lee JS, et al. One-day ex vivo culture allows effective gene transfer into human nonobese diabetic/severe combined im- mune-deficient repopulating cells using high-titer vesicular stomatitis virus G protein pseudotyped retrovirus. Blood. 1999;93:2217-2224.
  39. Joyce M, Roberts A, Sporn M, Bolander M. Trans- forming growth factor-␤ and the initiation of chon- drogenesis and osteogenesis in the rat femur. J Cell Biol. 1990;110:2195-2207.
  40. Centrella M, Horowitz M, Wozney J, McCarthy T. Transforming growth factor-␤ gene family mem- bers and bone. Endocr Rev. 1994;15:27-39.
  41. Frey B, Rafii S, Teterson M, Eaton D, Crystal R, Moore M. Adenovector-mediated expression of human thrombopoietin cDNA in immune-compro- mised mice: insights into the pathophysiology of osteomyelofibrosis. J Immunol. 1998;160:691-699.
  42. Crawford S, Stellmach V, Murphy-Ullrich J, et al. Thrombospondin-1 is a major activator of TGF-␤1 in vivo. Cell. 1998;93:1159-1170.
  43. Munger J, Huang X, Kawakatsu H, et al. The inte- grin ␣v␤6 binds and activates latent TGF␤1: a mechanism for regulating pulmonary inflamma- tion and fibrosis. Cell. 1999;96:319-328.

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Authors
Chagraoui, H., Komura, E., Tulliez, M., Giraudier, S., Vainchenker, W., & Wendling, F.
Affiliations
  • From INSERM U362, Institut Gustave Roussy, Villejuif, France; and Hôpital Cochin, Laboratoire d'Anatomopathologie, Paris, France.
  • Inserm (FR)
Corresponding author
Vainchenker, William
ORCID
Vainchenker, William
Venue
Blood
Publisher
American Society of Hematology
Published
2002-11-15
Volume
100
Issue
10
Pages
3495-3503
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood-2002-04-1133
OpenAlex
W2070075266
Cited by
238
References
3
Citations by year
2026: 9 · 2025: 3 · 2024: 9 · 2023: 8 · 2022: 9 · 2021: 12 · 2020: 13 · 2019: 8 · 2018: 4 · 2017: 13 · 2016: 10 · 2015: 9 · 2014: 9 · 2013: 7 · 2012: 8
FWCI
4.68
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed (publishedVersion)
Funders
Institut Gustave-Roussy
Topics
  • Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
Keywords
TGF-β1, thrombopoietin, myelofibrosis, myeloproliferative neoplasms, bone marrow fibrosis, retroviral transduction, bone marrow-derived stem cells, chimerism, extramedullary hematopoiesis, splenomegaly, thrombocytosis, reticular fibers
MeSH terms
Animals, Blood Platelets, Female, Graft Survival, Hematopoietic Stem Cells, Male, Myeloproliferative Disorders, Thrombopoietin, Transduction, Genetic, Transforming Growth Factor beta, Mice, Knockout, Hematopoietic Stem Cell Transplantation, Mice, Transforming Growth Factor beta1, Primary Myelofibrosis

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