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Notch pathway activation targets AML-initiating cell homeostasis and differentiation

Notch signaling pathway activation is known to contribute to the pathogenesis of a spectrum of human malignancies, including T cell leukemia. However, recent studies have implicated the Notch pathway as a tumor suppressor in myeloproliferative neoplasms and several solid tumors. Here we report a nov...

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Autores principales: Lobry, Camille, Ntziachristos, Panagiotis, Ndiaye-Lobry, Delphine, Oh, Philmo, Cimmino, Luisa, Zhu, Nan, Araldi, Elisa, Hu, Wenhuo, Freund, Jacquelyn, Abdel-Wahab, Omar, Ibrahim, Sherif, Skokos, Dimitris, Armstrong, Scott A., Levine, Ross L., Park, Christopher Y., Aifantis, Iannis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3570103/
https://www.ncbi.nlm.nih.gov/pubmed/23359070
http://dx.doi.org/10.1084/jem.20121484
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author Lobry, Camille
Ntziachristos, Panagiotis
Ndiaye-Lobry, Delphine
Oh, Philmo
Cimmino, Luisa
Zhu, Nan
Araldi, Elisa
Hu, Wenhuo
Freund, Jacquelyn
Abdel-Wahab, Omar
Ibrahim, Sherif
Skokos, Dimitris
Armstrong, Scott A.
Levine, Ross L.
Park, Christopher Y.
Aifantis, Iannis
author_facet Lobry, Camille
Ntziachristos, Panagiotis
Ndiaye-Lobry, Delphine
Oh, Philmo
Cimmino, Luisa
Zhu, Nan
Araldi, Elisa
Hu, Wenhuo
Freund, Jacquelyn
Abdel-Wahab, Omar
Ibrahim, Sherif
Skokos, Dimitris
Armstrong, Scott A.
Levine, Ross L.
Park, Christopher Y.
Aifantis, Iannis
author_sort Lobry, Camille
collection PubMed
description Notch signaling pathway activation is known to contribute to the pathogenesis of a spectrum of human malignancies, including T cell leukemia. However, recent studies have implicated the Notch pathway as a tumor suppressor in myeloproliferative neoplasms and several solid tumors. Here we report a novel tumor suppressor role for Notch signaling in acute myeloid leukemia (AML) and demonstrate that Notch pathway activation could represent a therapeutic strategy in this disease. We show that Notch signaling is silenced in human AML samples, as well as in AML-initiating cells in an animal model of the disease. In vivo activation of Notch signaling using genetic Notch gain of function models or in vitro using synthetic Notch ligand induces rapid cell cycle arrest, differentiation, and apoptosis of AML-initiating cells. Moreover, we demonstrate that Notch inactivation cooperates in vivo with loss of the myeloid tumor suppressor Tet2 to induce AML-like disease. These data demonstrate a novel tumor suppressor role for Notch signaling in AML and elucidate the potential therapeutic use of Notch receptor agonists in the treatment of this devastating leukemia.
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spelling pubmed-35701032013-08-11 Notch pathway activation targets AML-initiating cell homeostasis and differentiation Lobry, Camille Ntziachristos, Panagiotis Ndiaye-Lobry, Delphine Oh, Philmo Cimmino, Luisa Zhu, Nan Araldi, Elisa Hu, Wenhuo Freund, Jacquelyn Abdel-Wahab, Omar Ibrahim, Sherif Skokos, Dimitris Armstrong, Scott A. Levine, Ross L. Park, Christopher Y. Aifantis, Iannis J Exp Med Article Notch signaling pathway activation is known to contribute to the pathogenesis of a spectrum of human malignancies, including T cell leukemia. However, recent studies have implicated the Notch pathway as a tumor suppressor in myeloproliferative neoplasms and several solid tumors. Here we report a novel tumor suppressor role for Notch signaling in acute myeloid leukemia (AML) and demonstrate that Notch pathway activation could represent a therapeutic strategy in this disease. We show that Notch signaling is silenced in human AML samples, as well as in AML-initiating cells in an animal model of the disease. In vivo activation of Notch signaling using genetic Notch gain of function models or in vitro using synthetic Notch ligand induces rapid cell cycle arrest, differentiation, and apoptosis of AML-initiating cells. Moreover, we demonstrate that Notch inactivation cooperates in vivo with loss of the myeloid tumor suppressor Tet2 to induce AML-like disease. These data demonstrate a novel tumor suppressor role for Notch signaling in AML and elucidate the potential therapeutic use of Notch receptor agonists in the treatment of this devastating leukemia. The Rockefeller University Press 2013-02-11 /pmc/articles/PMC3570103/ /pubmed/23359070 http://dx.doi.org/10.1084/jem.20121484 Text en © 2013 Lobry et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Lobry, Camille
Ntziachristos, Panagiotis
Ndiaye-Lobry, Delphine
Oh, Philmo
Cimmino, Luisa
Zhu, Nan
Araldi, Elisa
Hu, Wenhuo
Freund, Jacquelyn
Abdel-Wahab, Omar
Ibrahim, Sherif
Skokos, Dimitris
Armstrong, Scott A.
Levine, Ross L.
Park, Christopher Y.
Aifantis, Iannis
Notch pathway activation targets AML-initiating cell homeostasis and differentiation
title Notch pathway activation targets AML-initiating cell homeostasis and differentiation
title_full Notch pathway activation targets AML-initiating cell homeostasis and differentiation
title_fullStr Notch pathway activation targets AML-initiating cell homeostasis and differentiation
title_full_unstemmed Notch pathway activation targets AML-initiating cell homeostasis and differentiation
title_short Notch pathway activation targets AML-initiating cell homeostasis and differentiation
title_sort notch pathway activation targets aml-initiating cell homeostasis and differentiation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3570103/
https://www.ncbi.nlm.nih.gov/pubmed/23359070
http://dx.doi.org/10.1084/jem.20121484
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