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TGF-β1 protein trap AVID200 beneficially affects hematopoiesis and bone marrow fibrosis in myelofibrosis
Myelofibrosis (MF) is a progressive chronic myeloproliferative neoplasm characterized by hyperactivation of JAK/STAT signaling and dysregulation of the transcription factor GATA1 in megakaryocytes (MKs). TGF-β plays a pivotal role in the pathobiology of MF by promoting BM fibrosis and collagen depos...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492354/ https://www.ncbi.nlm.nih.gov/pubmed/34383713 http://dx.doi.org/10.1172/jci.insight.145651 |
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author | Varricchio, Lilian Iancu-Rubin, Camelia Upadhyaya, Bhaskar Zingariello, Maria Martelli, Fabrizio Verachi, Paola Clementelli, Cara Denis, Jean-Francois Rahman, Adeeb H. Tremblay, Gilles Mascarenhas, John Mesa, Ruben A. O’Connor-McCourt, Maureen Migliaccio, Anna Rita Hoffman, Ronald |
author_facet | Varricchio, Lilian Iancu-Rubin, Camelia Upadhyaya, Bhaskar Zingariello, Maria Martelli, Fabrizio Verachi, Paola Clementelli, Cara Denis, Jean-Francois Rahman, Adeeb H. Tremblay, Gilles Mascarenhas, John Mesa, Ruben A. O’Connor-McCourt, Maureen Migliaccio, Anna Rita Hoffman, Ronald |
author_sort | Varricchio, Lilian |
collection | PubMed |
description | Myelofibrosis (MF) is a progressive chronic myeloproliferative neoplasm characterized by hyperactivation of JAK/STAT signaling and dysregulation of the transcription factor GATA1 in megakaryocytes (MKs). TGF-β plays a pivotal role in the pathobiology of MF by promoting BM fibrosis and collagen deposition and by enhancing the dormancy of normal hematopoietic stem cells (HSCs). In this study, we show that MF-MKs elaborated significantly greater levels of TGF-β1 than TGF-β2 and TGF-β3 to a varying degree, and we evaluated the ability of AVID200, a potent TGF-β1/TGF-β3 protein trap, to block the excessive TGF-β signaling. Treatment of human mesenchymal stromal cells with AVID200 significantly reduced their proliferation, decreased phosphorylation of SMAD2, and interfered with the ability of TGF-β1 to induce collagen expression. Moreover, treatment of MF mononuclear cells with AVID200 led to increased numbers of progenitor cells (PCs) with WT JAK2 rather than mutated JAK2V617F. This effect of AVID200 on MF PCs was attributed to its ability to block TGF-β1–induced p57(Kip2) expression and SMAD2 activation, thereby allowing normal rather than MF PCs to preferentially proliferate and form hematopoietic colonies. To assess the in vivo effects of AVID200, Gata1(lo) mice, a murine model of MF, were treated with AVID200, resulting in the reduction in BM fibrosis and an increase in BM cellularity. AVID200 treatment also increased the frequency and numbers of murine progenitor cells as well as short-term and long-term HSCs. Collectively, these data provide the rationale for TGF-β1 blockade, with AVID200 as a therapeutic strategy for patients with MF. |
format | Online Article Text |
id | pubmed-8492354 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-84923542021-10-07 TGF-β1 protein trap AVID200 beneficially affects hematopoiesis and bone marrow fibrosis in myelofibrosis Varricchio, Lilian Iancu-Rubin, Camelia Upadhyaya, Bhaskar Zingariello, Maria Martelli, Fabrizio Verachi, Paola Clementelli, Cara Denis, Jean-Francois Rahman, Adeeb H. Tremblay, Gilles Mascarenhas, John Mesa, Ruben A. O’Connor-McCourt, Maureen Migliaccio, Anna Rita Hoffman, Ronald JCI Insight Research Article Myelofibrosis (MF) is a progressive chronic myeloproliferative neoplasm characterized by hyperactivation of JAK/STAT signaling and dysregulation of the transcription factor GATA1 in megakaryocytes (MKs). TGF-β plays a pivotal role in the pathobiology of MF by promoting BM fibrosis and collagen deposition and by enhancing the dormancy of normal hematopoietic stem cells (HSCs). In this study, we show that MF-MKs elaborated significantly greater levels of TGF-β1 than TGF-β2 and TGF-β3 to a varying degree, and we evaluated the ability of AVID200, a potent TGF-β1/TGF-β3 protein trap, to block the excessive TGF-β signaling. Treatment of human mesenchymal stromal cells with AVID200 significantly reduced their proliferation, decreased phosphorylation of SMAD2, and interfered with the ability of TGF-β1 to induce collagen expression. Moreover, treatment of MF mononuclear cells with AVID200 led to increased numbers of progenitor cells (PCs) with WT JAK2 rather than mutated JAK2V617F. This effect of AVID200 on MF PCs was attributed to its ability to block TGF-β1–induced p57(Kip2) expression and SMAD2 activation, thereby allowing normal rather than MF PCs to preferentially proliferate and form hematopoietic colonies. To assess the in vivo effects of AVID200, Gata1(lo) mice, a murine model of MF, were treated with AVID200, resulting in the reduction in BM fibrosis and an increase in BM cellularity. AVID200 treatment also increased the frequency and numbers of murine progenitor cells as well as short-term and long-term HSCs. Collectively, these data provide the rationale for TGF-β1 blockade, with AVID200 as a therapeutic strategy for patients with MF. American Society for Clinical Investigation 2021-09-22 /pmc/articles/PMC8492354/ /pubmed/34383713 http://dx.doi.org/10.1172/jci.insight.145651 Text en © 2021 Varricchio et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Varricchio, Lilian Iancu-Rubin, Camelia Upadhyaya, Bhaskar Zingariello, Maria Martelli, Fabrizio Verachi, Paola Clementelli, Cara Denis, Jean-Francois Rahman, Adeeb H. Tremblay, Gilles Mascarenhas, John Mesa, Ruben A. O’Connor-McCourt, Maureen Migliaccio, Anna Rita Hoffman, Ronald TGF-β1 protein trap AVID200 beneficially affects hematopoiesis and bone marrow fibrosis in myelofibrosis |
title | TGF-β1 protein trap AVID200 beneficially affects hematopoiesis and bone marrow fibrosis in myelofibrosis |
title_full | TGF-β1 protein trap AVID200 beneficially affects hematopoiesis and bone marrow fibrosis in myelofibrosis |
title_fullStr | TGF-β1 protein trap AVID200 beneficially affects hematopoiesis and bone marrow fibrosis in myelofibrosis |
title_full_unstemmed | TGF-β1 protein trap AVID200 beneficially affects hematopoiesis and bone marrow fibrosis in myelofibrosis |
title_short | TGF-β1 protein trap AVID200 beneficially affects hematopoiesis and bone marrow fibrosis in myelofibrosis |
title_sort | tgf-β1 protein trap avid200 beneficially affects hematopoiesis and bone marrow fibrosis in myelofibrosis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492354/ https://www.ncbi.nlm.nih.gov/pubmed/34383713 http://dx.doi.org/10.1172/jci.insight.145651 |
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