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Disruption of gap junctions attenuates acute myeloid leukemia chemoresistance induced by bone marrow mesenchymal stromal cells
The bone marrow (BM) niche impacts the progression of acute myeloid leukemia (AML) by favoring the chemoresistance of AML cells. Intimate interactions between leukemic cells and BM mesenchymal stromal cells (BM-MSCs) play key roles in this process. Direct intercellular communications between hematop...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002301/ https://www.ncbi.nlm.nih.gov/pubmed/31649334 http://dx.doi.org/10.1038/s41388-019-1069-y |
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author | Kouzi, Farah Zibara, Kazem Bourgeais, Jerome Picou, Frederic Gallay, Nathalie Brossaud, Julie Dakik, Hassan Roux, Benjamin Hamard, Sophie Le Nail, Louis-Romee Hleihel, Rita Foucault, Amelie Ravalet, Noemie Rouleux-Bonnin, Florence Gouilleux, Fabrice Mazurier, Frederic Bene, Marie C. Akl, Haidar Gyan, Emmanuel Domenech, Jorge El-Sabban, Marwan Herault, Olivier |
author_facet | Kouzi, Farah Zibara, Kazem Bourgeais, Jerome Picou, Frederic Gallay, Nathalie Brossaud, Julie Dakik, Hassan Roux, Benjamin Hamard, Sophie Le Nail, Louis-Romee Hleihel, Rita Foucault, Amelie Ravalet, Noemie Rouleux-Bonnin, Florence Gouilleux, Fabrice Mazurier, Frederic Bene, Marie C. Akl, Haidar Gyan, Emmanuel Domenech, Jorge El-Sabban, Marwan Herault, Olivier |
author_sort | Kouzi, Farah |
collection | PubMed |
description | The bone marrow (BM) niche impacts the progression of acute myeloid leukemia (AML) by favoring the chemoresistance of AML cells. Intimate interactions between leukemic cells and BM mesenchymal stromal cells (BM-MSCs) play key roles in this process. Direct intercellular communications between hematopoietic cells and BM-MSCs involve connexins, components of gap junctions. We postulated that blocking gap junction assembly could modify cell–cell interactions in the leukemic niche and consequently the chemoresistance. The comparison of BM-MSCs from AML patients and healthy donors revealed a specific profile of connexins in BM-MSCs of the leukemic niche and the effects of carbenoxolone (CBX), a gap junction disruptor, were evaluated on AML cells. CBX presents an antileukemic effect without affecting normal BM-CD34(+) progenitor cells. The proapoptotic effect of CBX on AML cells is in line with the extinction of energy metabolism. CBX acts synergistically with cytarabine (Ara-C) in vitro and in vivo. Coculture experiments of AML cells with BM-MSCs revealed that CBX neutralizes the protective effect of the niche against the Ara-C-induced apoptosis of leukemic cells. Altogether, these results suggest that CBX could be of therapeutic interest to reduce the chemoresistance favored by the leukemic niche, by targeting gap junctions, without affecting normal hematopoiesis. |
format | Online Article Text |
id | pubmed-7002301 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-70023012020-02-07 Disruption of gap junctions attenuates acute myeloid leukemia chemoresistance induced by bone marrow mesenchymal stromal cells Kouzi, Farah Zibara, Kazem Bourgeais, Jerome Picou, Frederic Gallay, Nathalie Brossaud, Julie Dakik, Hassan Roux, Benjamin Hamard, Sophie Le Nail, Louis-Romee Hleihel, Rita Foucault, Amelie Ravalet, Noemie Rouleux-Bonnin, Florence Gouilleux, Fabrice Mazurier, Frederic Bene, Marie C. Akl, Haidar Gyan, Emmanuel Domenech, Jorge El-Sabban, Marwan Herault, Olivier Oncogene Article The bone marrow (BM) niche impacts the progression of acute myeloid leukemia (AML) by favoring the chemoresistance of AML cells. Intimate interactions between leukemic cells and BM mesenchymal stromal cells (BM-MSCs) play key roles in this process. Direct intercellular communications between hematopoietic cells and BM-MSCs involve connexins, components of gap junctions. We postulated that blocking gap junction assembly could modify cell–cell interactions in the leukemic niche and consequently the chemoresistance. The comparison of BM-MSCs from AML patients and healthy donors revealed a specific profile of connexins in BM-MSCs of the leukemic niche and the effects of carbenoxolone (CBX), a gap junction disruptor, were evaluated on AML cells. CBX presents an antileukemic effect without affecting normal BM-CD34(+) progenitor cells. The proapoptotic effect of CBX on AML cells is in line with the extinction of energy metabolism. CBX acts synergistically with cytarabine (Ara-C) in vitro and in vivo. Coculture experiments of AML cells with BM-MSCs revealed that CBX neutralizes the protective effect of the niche against the Ara-C-induced apoptosis of leukemic cells. Altogether, these results suggest that CBX could be of therapeutic interest to reduce the chemoresistance favored by the leukemic niche, by targeting gap junctions, without affecting normal hematopoiesis. Nature Publishing Group UK 2019-10-24 2020 /pmc/articles/PMC7002301/ /pubmed/31649334 http://dx.doi.org/10.1038/s41388-019-1069-y Text en © The Author(s) 2019 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Kouzi, Farah Zibara, Kazem Bourgeais, Jerome Picou, Frederic Gallay, Nathalie Brossaud, Julie Dakik, Hassan Roux, Benjamin Hamard, Sophie Le Nail, Louis-Romee Hleihel, Rita Foucault, Amelie Ravalet, Noemie Rouleux-Bonnin, Florence Gouilleux, Fabrice Mazurier, Frederic Bene, Marie C. Akl, Haidar Gyan, Emmanuel Domenech, Jorge El-Sabban, Marwan Herault, Olivier Disruption of gap junctions attenuates acute myeloid leukemia chemoresistance induced by bone marrow mesenchymal stromal cells |
title | Disruption of gap junctions attenuates acute myeloid leukemia chemoresistance induced by bone marrow mesenchymal stromal cells |
title_full | Disruption of gap junctions attenuates acute myeloid leukemia chemoresistance induced by bone marrow mesenchymal stromal cells |
title_fullStr | Disruption of gap junctions attenuates acute myeloid leukemia chemoresistance induced by bone marrow mesenchymal stromal cells |
title_full_unstemmed | Disruption of gap junctions attenuates acute myeloid leukemia chemoresistance induced by bone marrow mesenchymal stromal cells |
title_short | Disruption of gap junctions attenuates acute myeloid leukemia chemoresistance induced by bone marrow mesenchymal stromal cells |
title_sort | disruption of gap junctions attenuates acute myeloid leukemia chemoresistance induced by bone marrow mesenchymal stromal cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002301/ https://www.ncbi.nlm.nih.gov/pubmed/31649334 http://dx.doi.org/10.1038/s41388-019-1069-y |
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