title: Adenoviral-mediated TGF-beta1 inhibition in a mouse model of myelofibrosis inhibit bone marrow fibrosis development.
abstract: 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.
authors.affiliation: INSERM U790, Pavillon de recherche 1, Institut Gustave Roussy, Villejuif Cedex, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gastinne
authors.forename: Frédéric
authors.initials: F
authors.lastname: Vigant
authors.forename: Cecile
authors.initials: C
authors.lastname: Lavenu-Bombled
authors.forename: Orianne
authors.initials: O
authors.lastname: Wagner-Ballon
authors.forename: Micheline
authors.initials: M
authors.lastname: Tulliez
authors.forename: Hédia
authors.initials: H
authors.lastname: Chagraoui
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Villeval
authors.forename: Catherine
authors.initials: C
authors.lastname: Lacout
authors.forename: Michel
authors.initials: M
authors.lastname: Perricaudet
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.forename: Karim
authors.initials: K
authors.lastname: Benihoud
authors.forename: Stéphane
authors.initials: S
authors.lastname: Giraudier
mesh_terms: D000256:Adenoviridae; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D051379:Mice; D016513:Mice, SCID; D055728:Primary Myelofibrosis / Q000517:prevention & control / Q000628:therapy*; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D013158:Splenic Diseases / Q000628:therapy; D016019:Survival Analysis; D013926:Thrombopoietin / Q000008:administration & dosage / Q000235:genetics; D014161:Transduction, Genetic; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors*; D014185:Transplantation, Isogeneic
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D013926:Thrombopoietin; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II