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A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome

In a significant number of cases cancer therapy is followed by a resurgence of more aggressive tumors derived from immature cells. One example is acute myeloid leukemia (AML), where an accumulation of immature cells is responsible for relapse following treatment. We previously demonstrated in chroni...

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Autores principales: Voeltzel, Thibault, Flores-Violante, Mario, Zylbersztejn, Florence, Lefort, Sylvain, Billandon, Marion, Jeanpierre, Sandrine, Joly, Stéphane, Fossard, Gaelle, Milenkov, Milen, Mazurier, Frédéric, Nehme, Ali, Belhabri, Amine, Paubelle, Etienne, Thomas, Xavier, Michallet, Mauricette, Louache, Fawzia, Nicolini, Franck-Emmanuel, Caron de Fromentel, Claude, Maguer-Satta, Véronique
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160490/
https://www.ncbi.nlm.nih.gov/pubmed/30262802
http://dx.doi.org/10.1038/s41419-018-1042-7
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author Voeltzel, Thibault
Flores-Violante, Mario
Zylbersztejn, Florence
Lefort, Sylvain
Billandon, Marion
Jeanpierre, Sandrine
Joly, Stéphane
Fossard, Gaelle
Milenkov, Milen
Mazurier, Frédéric
Nehme, Ali
Belhabri, Amine
Paubelle, Etienne
Thomas, Xavier
Michallet, Mauricette
Louache, Fawzia
Nicolini, Franck-Emmanuel
Caron de Fromentel, Claude
Maguer-Satta, Véronique
author_facet Voeltzel, Thibault
Flores-Violante, Mario
Zylbersztejn, Florence
Lefort, Sylvain
Billandon, Marion
Jeanpierre, Sandrine
Joly, Stéphane
Fossard, Gaelle
Milenkov, Milen
Mazurier, Frédéric
Nehme, Ali
Belhabri, Amine
Paubelle, Etienne
Thomas, Xavier
Michallet, Mauricette
Louache, Fawzia
Nicolini, Franck-Emmanuel
Caron de Fromentel, Claude
Maguer-Satta, Véronique
author_sort Voeltzel, Thibault
collection PubMed
description In a significant number of cases cancer therapy is followed by a resurgence of more aggressive tumors derived from immature cells. One example is acute myeloid leukemia (AML), where an accumulation of immature cells is responsible for relapse following treatment. We previously demonstrated in chronic myeloid leukemia that the bone morphogenetic proteins (BMP) pathway is involved in stem cell fate and contributes to transformation, expansion, and persistence of leukemic stem cells. Here, we have identified intrinsic and extrinsic dysregulations of the BMP pathway in AML patients at diagnosis. BMP2 and BMP4 protein concentrations are elevated within patients’ bone marrow with a BMP4-dominant availability. This overproduction likely depends on the bone marrow microenvironment, since MNCs do not overexpress BMP4 transcripts. Intrinsically, the receptor BMPR1A transcript is increased in leukemic samples with more cells presenting this receptor at the membrane. This high expression of BMPR1A is further increased upon BMP4 exposure, specifically in AML cells. Downstream analysis demonstrated that BMP4 controls the expression of the survival factor ΔNp73 through its binding to BMPR1A. At the functional level, this results in the direct induction of NANOG expression and an increase of stem-like features in leukemic cells, as shown by ALDH and functional assays. In addition, we identified for the first time a strong correlation between ΔNp73, BMPR1A and NANOG expression with patient outcome. These results highlight a new signaling cascade initiated by tumor environment alterations leading to stem-cell features and poor patients’ outcome.
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spelling pubmed-61604902018-10-01 A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome Voeltzel, Thibault Flores-Violante, Mario Zylbersztejn, Florence Lefort, Sylvain Billandon, Marion Jeanpierre, Sandrine Joly, Stéphane Fossard, Gaelle Milenkov, Milen Mazurier, Frédéric Nehme, Ali Belhabri, Amine Paubelle, Etienne Thomas, Xavier Michallet, Mauricette Louache, Fawzia Nicolini, Franck-Emmanuel Caron de Fromentel, Claude Maguer-Satta, Véronique Cell Death Dis Article In a significant number of cases cancer therapy is followed by a resurgence of more aggressive tumors derived from immature cells. One example is acute myeloid leukemia (AML), where an accumulation of immature cells is responsible for relapse following treatment. We previously demonstrated in chronic myeloid leukemia that the bone morphogenetic proteins (BMP) pathway is involved in stem cell fate and contributes to transformation, expansion, and persistence of leukemic stem cells. Here, we have identified intrinsic and extrinsic dysregulations of the BMP pathway in AML patients at diagnosis. BMP2 and BMP4 protein concentrations are elevated within patients’ bone marrow with a BMP4-dominant availability. This overproduction likely depends on the bone marrow microenvironment, since MNCs do not overexpress BMP4 transcripts. Intrinsically, the receptor BMPR1A transcript is increased in leukemic samples with more cells presenting this receptor at the membrane. This high expression of BMPR1A is further increased upon BMP4 exposure, specifically in AML cells. Downstream analysis demonstrated that BMP4 controls the expression of the survival factor ΔNp73 through its binding to BMPR1A. At the functional level, this results in the direct induction of NANOG expression and an increase of stem-like features in leukemic cells, as shown by ALDH and functional assays. In addition, we identified for the first time a strong correlation between ΔNp73, BMPR1A and NANOG expression with patient outcome. These results highlight a new signaling cascade initiated by tumor environment alterations leading to stem-cell features and poor patients’ outcome. Nature Publishing Group UK 2018-09-27 /pmc/articles/PMC6160490/ /pubmed/30262802 http://dx.doi.org/10.1038/s41419-018-1042-7 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Voeltzel, Thibault
Flores-Violante, Mario
Zylbersztejn, Florence
Lefort, Sylvain
Billandon, Marion
Jeanpierre, Sandrine
Joly, Stéphane
Fossard, Gaelle
Milenkov, Milen
Mazurier, Frédéric
Nehme, Ali
Belhabri, Amine
Paubelle, Etienne
Thomas, Xavier
Michallet, Mauricette
Louache, Fawzia
Nicolini, Franck-Emmanuel
Caron de Fromentel, Claude
Maguer-Satta, Véronique
A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome
title A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome
title_full A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome
title_fullStr A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome
title_full_unstemmed A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome
title_short A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome
title_sort new signaling cascade linking bmp4, bmpr1a, δnp73 and nanog impacts on stem-like human cell properties and patient outcome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160490/
https://www.ncbi.nlm.nih.gov/pubmed/30262802
http://dx.doi.org/10.1038/s41419-018-1042-7
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