Characterization of the TGF-β1 signaling abnormalities in the Gata1low mouse model of myelofibrosis
Copyright policy )Characterization of the TGF-β1 signaling abnormalities in the Gata1low mouse model of myelofibrosis
Key PointsAbnormal 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.
Adult, Male, Gene Expression Profiling, Blotting, Western, Middle Aged, 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 Gata1(low) 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 Gata1(low) 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 Gata1(low) 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 Gata1(low) mice and may represent additional targets for therapeutic intervention in PMF., Flow Cytometry, Chemokine CXCL12, Disease Models, Animal, Mice, Bone Marrow, Primary Myelofibrosis, Case-Control Studies, GROWTH-FACTOR-BETA; HEMATOPOIETIC STEM-CELLS; BONE-MARROW FIBROSIS; TGF-BETA; MYELOID METAPLASIA; IDIOPATHIC MYELOFIBROSIS; GATA-1(LOW) MICE; MEGAKARYOCYTES; EXPRESSION; RECEPTORS, Biomarkers, Tumor, Animals, Cytokines, Humans, GATA1 Transcription Factor, RNA, Messenger, RNA, Small Interfering, Oligonucleotide Array Sequence Analysis
Adult, Male, Gene Expression Profiling, Blotting, Western, Middle Aged, 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 Gata1(low) 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 Gata1(low) 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 Gata1(low) 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 Gata1(low) mice and may represent additional targets for therapeutic intervention in PMF., Flow Cytometry, Chemokine CXCL12, Disease Models, Animal, Mice, Bone Marrow, Primary Myelofibrosis, Case-Control Studies, GROWTH-FACTOR-BETA; HEMATOPOIETIC STEM-CELLS; BONE-MARROW FIBROSIS; TGF-BETA; MYELOID METAPLASIA; IDIOPATHIC MYELOFIBROSIS; GATA-1(LOW) MICE; MEGAKARYOCYTES; EXPRESSION; RECEPTORS, Biomarkers, Tumor, Animals, Cytokines, Humans, GATA1 Transcription Factor, RNA, Messenger, RNA, Small Interfering, Oligonucleotide Array Sequence Analysis
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