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

Maria Zingariello, Fabrizio Martelli, Fiorella Ciaffoni, Francesca Masiello, Barbara Ghinassi, Emanuela D'Amore, Margherita Massa, Giovanni Barosi, Laura Sancillo, Xiaochun Li, Judith D. Goldberg, Rosa Alba Rana, Anna Rita Migliaccio

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)3345-3363
Number of pages19
JournalBlood
Volume121
Issue number17
DOIs
Publication statusPublished - Apr 25 2013

    Fingerprint

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Zingariello, M., Martelli, F., Ciaffoni, F., Masiello, F., Ghinassi, B., D'Amore, E., Massa, M., Barosi, G., Sancillo, L., Li, X., Goldberg, J. D., Rana, R. A., & Migliaccio, A. R. (2013). Characterization of the TGF-β1 signaling abnormalities in the Gata1low mouse model of myelofibrosis. Blood, 121(17), 3345-3363. https://doi.org/10.1182/blood-2012-06-439661