Characterization of the TGF-β1 signaling abnormalities in the Gata1low mouse model of myelofibrosis

• Published in: Blood 2013-04, Vol.121 (17), p.3345-3363
• Main Authors: Zingariello, Maria, Martelli, Fabrizio, Ciaffoni, Fiorella, Masiello, Francesca, Ghinassi, Barbara, D'Amore, Emanuela, Massa, Margherita, Barosi, Giovanni, Sancillo, Laura, Li, Xiaochun, Goldberg, Judith D., Rana, Rosa Alba, Migliaccio, Anna Rita
• Format: Article
• Language: English
• Subjects: Adult; Animals; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Blotting, Western; Bone Marrow - metabolism; Bone Marrow - pathology; Case-Control Studies; Chemokine CXCL12 - genetics; Chemokine CXCL12 - metabolism; Cytokines - metabolism; Disease Models, Animal; Flow Cytometry; GATA1 Transcription Factor - physiology; Gene Expression Profiling; Hematopoiesis and Stem Cells; Humans; Male; Mice; Middle Aged; Oligonucleotide Array Sequence Analysis; Primary Myelofibrosis - etiology; Primary Myelofibrosis - metabolism; Primary Myelofibrosis - pathology; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Signal Transduction; Spleen - metabolism; Spleen - pathology; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Transforming Growth Factor beta1 - antagonists & inhibitors; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-06-439661

Primary myelofibrosis (PMF) is characterized by fibrosis, ineffective hematopoiesis in marrow, and hematopoiesis in extramedullary sites and is associated with abnormal megakaryocyte (MK) development and increased transforming growth factor (TGF)-β1 release. To clarify the role of TGF-β1 in the pathogenesis of this disease, the TGF-β1 signaling pathway of marrow and spleen of the Gata1low mouse model of myelofibrosis (MF) was profiled and the consequences of inhibition of TGF-β1 signaling on disease manifestations determined. The expression of 20 genes in marrow and 36 genes in spleen of Gata1low mice was altered. David-pathway analyses identified alterations of TGF-β1, Hedgehog, and p53 signaling in marrow and spleen and of mammalian target of rapamycin (mTOR) in spleen only and predicted that these alterations would induce consequences consistent with the Gata1low phenotype (increased apoptosis and G1 arrest both in marrow and spleen and increased osteoblast differentiation and reduced ubiquitin-mediated proteolysis in marrow only). Inhibition of TGF-β1 signaling normalized the expression of p53-related genes, restoring hematopoiesis and MK development and reducing fibrosis, neovascularization, and osteogenesis in marrow. It also normalized p53/mTOR/Hedgehog-related genes in spleen, reducing extramedullary hematopoiesis. These data identify altered expression signatures of TGF-β1 signaling that may be responsible for MF in Gata1low mice and may represent additional targets for therapeutic intervention in PMF. •Abnormal signatures in TGF-β1 signaling gene expression were identified in spleen and marrow from the Gata1low model of MF.•These signatures include abnormalities in individual gene (Id2, Stat1, mTOR) in spleen and of gene pathways (Smads and BMPs) in marrow.