TY - JOUR
T1 - Adenoviral-mediated TGF-β1 inhibition in a mouse model of myelofibrosis inhibit bone marrow fibrosis development
AU - Gastinne, Thomas
AU - Vigant, Frédéric
AU - Lavenu-Bombled, Cecile
AU - Wagner-Ballon, Orianne
AU - Tulliez, Micheline
AU - Chagraoui, Hédia
AU - Villeval, Jean Luc
AU - Lacout, Catherine
AU - Perricaudet, Michel
AU - Vainchenker, William
AU - Benihoud, Karim
AU - Giraudier, Stéphane
N1 - Funding Information:
The authors are grateful to Caroline Lefebvre for helpful discussions and improving the English manuscript and to Annie Rouchès and Patrice Ardouin for the mice management. Supported by grants from the INSERM and la Ligue Nationale contre le Cancer “équipe labellisée 2004” and fellowships from the FRM (Fondation pour la recherche médicale) (T.G.), l'ARC (Association pour la Recherche contre le Cancer), INSERM (O.W.B), and the Research Ministry (H.C).
PY - 2007/1/1
Y1 - 2007/1/1
N2 - 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)-β1 released by hematopoietic cells in the onset of myelofibrosis. The purpose of this study was to investigate whether TGF-β1 inhibition could directly inhibit fibrosis development in a curative approach of this mice model. An adenovirus encoding for TGF-β1 soluble receptor (TGF-β-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-β-RII-Fc was detected in the blood of all treated mice, leading to a dramatic decrease in TGF-β1 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.
AB - 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)-β1 released by hematopoietic cells in the onset of myelofibrosis. The purpose of this study was to investigate whether TGF-β1 inhibition could directly inhibit fibrosis development in a curative approach of this mice model. An adenovirus encoding for TGF-β1 soluble receptor (TGF-β-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-β-RII-Fc was detected in the blood of all treated mice, leading to a dramatic decrease in TGF-β1 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.
UR - http://www.scopus.com/inward/record.url?scp=33845869864&partnerID=8YFLogxK
U2 - 10.1016/j.exphem.2006.08.016
DO - 10.1016/j.exphem.2006.08.016
M3 - Article
C2 - 17198875
AN - SCOPUS:33845869864
SN - 0301-472X
VL - 35
SP - 64
EP - 74
JO - Experimental Hematology
JF - Experimental Hematology
IS - 1
ER -