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Characterization of the TGF-beta1 signaling abnormalities in the Gata1low mouse model of myelofibrosis.

Authors: Zingariello, M  Martelli, F  Ciaffoni, F  Masiello, F  Ghinassi, B  D'Amore, E  Massa, M  Barosi, G  Sancillo, L  Li, X  Goldberg, JD  Rana, RA  Migliaccio, AR 
Citation: Zingariello M, etal., Blood. 2013 Apr 25;121(17):3345-63. doi: 10.1182/blood-2012-06-439661. Epub 2013 Mar 5.
Pubmed: (View Article at PubMed) PMID:23462118
DOI: Full-text: 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)-beta1 release. To clarify the role of TGF-beta1 in the pathogenesis of this disease, the TGF-beta1 signaling pathway of marrow and spleen of the Gata1(low) mouse model of myelofibrosis (MF) was profiled and the consequences of inhibition of TGF-beta1 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-beta1, 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-beta1 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-beta1 signaling that may be responsible for MF in Gata1(low) mice and may represent additional targets for therapeutic intervention in PMF.

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CRRD Object Information
CRRD ID: 11073609
Created: 2016-04-29
Species: All species
Last Modified: 2016-04-29
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.