Adenoviral-mediated TGF-beta1 inhibition in a mouse model of myelofibrosis inhibit bone marrow fibrosis development

Exp Hematol. 2007 Jan;35(1):64-74. doi: 10.1016/j.exphem.2006.08.016.


Myelofibrosis is characterized by excessive deposits of extracellular matrix proteins, which occur as a marrow microenvironment reactive response to cytokines released from the clonal malignant myeloproliferation. The observation that mice exposed to high systemic levels of thrombopoietin (TPO) invariably developing myelofibrosis has allowed demonstration of the crucial role of transforming growth factor (TGF)-beta1 released by hematopoietic cells in the onset of myelofibrosis. The purpose of this study was to investigate whether TGF-beta1 inhibition could directly inhibit fibrosis development in a curative approach of this mice model. An adenovirus encoding for TGF-beta1 soluble receptor (TGF-beta-RII-Fc) was injected either shortly after transplantation (preventive) or 30 days post-transplantation (curative). Mice were transplanted with syngenic bone marrow cells transduced with a retrovirus encoding for murine TPO. All mice developed a myeloproliferative syndrome. TGF-beta-RII-Fc was detected in the blood of all treated mice, leading to a dramatic decrease in TGF-beta1 level. Histological analysis show that the two approaches (curative or preventive) were successful enough to inhibit bone marrow and spleen fibrosis development in this model. However, lethality of TPO overexpression was not decreased after treatment, indicating that in this mice model, myeloproliferation rather than fibrosis was probably responsible for the lethality induced by the disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae
  • Animals
  • Bone Marrow Cells / metabolism
  • Bone Marrow Transplantation
  • Disease Models, Animal
  • Genetic Therapy / methods*
  • Mice
  • Mice, SCID
  • Primary Myelofibrosis / prevention & control
  • Primary Myelofibrosis / therapy*
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / administration & dosage*
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / therapeutic use
  • Splenic Diseases / therapy
  • Survival Analysis
  • Thrombopoietin / administration & dosage
  • Thrombopoietin / genetics
  • Transduction, Genetic
  • Transforming Growth Factor beta1 / antagonists & inhibitors*
  • Transplantation, Isogeneic


  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Thrombopoietin
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II