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Differential regulation of cell death pathways by the microenvironment correlates with chemoresistance and survival in leukaemia

Glucocorticoids (GCs) and topoisomerase II inhibitors are used to treat acute lymphoblastic leukaemia (ALL) as they induce death in lymphoid cells through the glucocorticoid receptor (GR) and p53 respectively. Mechanisms underlying ALL cell death and the contribution of the bone marrow microenvironm...

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Autores principales: Qattan, Malak Yahia, Bakker, Emyr Yosef, Rajendran, Ramkumar, Chen, Daphne Wei-Chen, Saha, Vaskar, Liu, Jizhong, Zeef, Leo, Schwartz, Jean-Marc, Mutti, Luciano, Demonacos, Constantinos, Krstic-Demonacos, Marija
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5459454/
https://www.ncbi.nlm.nih.gov/pubmed/28582465
http://dx.doi.org/10.1371/journal.pone.0178606
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author Qattan, Malak Yahia
Bakker, Emyr Yosef
Rajendran, Ramkumar
Chen, Daphne Wei-Chen
Saha, Vaskar
Liu, Jizhong
Zeef, Leo
Schwartz, Jean-Marc
Mutti, Luciano
Demonacos, Constantinos
Krstic-Demonacos, Marija
author_facet Qattan, Malak Yahia
Bakker, Emyr Yosef
Rajendran, Ramkumar
Chen, Daphne Wei-Chen
Saha, Vaskar
Liu, Jizhong
Zeef, Leo
Schwartz, Jean-Marc
Mutti, Luciano
Demonacos, Constantinos
Krstic-Demonacos, Marija
author_sort Qattan, Malak Yahia
collection PubMed
description Glucocorticoids (GCs) and topoisomerase II inhibitors are used to treat acute lymphoblastic leukaemia (ALL) as they induce death in lymphoid cells through the glucocorticoid receptor (GR) and p53 respectively. Mechanisms underlying ALL cell death and the contribution of the bone marrow microenvironment to drug response/resistance remain unclear. The role of the microenvironment and the identification of chemoresistance determinants were studied by transcriptomic analysis in ALL cells treated with Dexamethasone (Dex), and Etoposide (Etop) grown in the presence or absence of bone marrow conditioned media (CM). The necroptotic (RIPK1) and the apoptotic (caspase-8/3) markers were downregulated by CM, whereas the inhibitory effects of chemotherapy on the autophagy marker Beclin-1 (BECN1) were reduced suggesting CM exerts cytoprotective effects. GCs upregulated the RIPK1 ubiquitinating factor BIRC3 (cIAP2), in GC-sensitive (CEM-C7-14) but not in resistant (CEM-C1-15) cells. In addition, CM selectively affected GR phosphorylation in a site and cell-specific manner. GR is recruited to RIPK1, BECN1 and BIRC3 promoters in the sensitive but not in the resistant cells with phosphorylated GR forms being generally less recruited in the presence of hormone. FACS analysis and caspase-8 assays demonstrated that CM promoted a pro-survival trend. High molecular weight proteins reacting with the RIPK1 antibody were modified upon incubation with the BIRC3 inhibitor AT406 in CEM-C7-14 cells suggesting that they represent ubiquitinated forms of RIPK1. Our data suggest that there is a correlation between microenvironment-induced ALL proliferation and altered response to chemotherapy.
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spelling pubmed-54594542017-06-15 Differential regulation of cell death pathways by the microenvironment correlates with chemoresistance and survival in leukaemia Qattan, Malak Yahia Bakker, Emyr Yosef Rajendran, Ramkumar Chen, Daphne Wei-Chen Saha, Vaskar Liu, Jizhong Zeef, Leo Schwartz, Jean-Marc Mutti, Luciano Demonacos, Constantinos Krstic-Demonacos, Marija PLoS One Research Article Glucocorticoids (GCs) and topoisomerase II inhibitors are used to treat acute lymphoblastic leukaemia (ALL) as they induce death in lymphoid cells through the glucocorticoid receptor (GR) and p53 respectively. Mechanisms underlying ALL cell death and the contribution of the bone marrow microenvironment to drug response/resistance remain unclear. The role of the microenvironment and the identification of chemoresistance determinants were studied by transcriptomic analysis in ALL cells treated with Dexamethasone (Dex), and Etoposide (Etop) grown in the presence or absence of bone marrow conditioned media (CM). The necroptotic (RIPK1) and the apoptotic (caspase-8/3) markers were downregulated by CM, whereas the inhibitory effects of chemotherapy on the autophagy marker Beclin-1 (BECN1) were reduced suggesting CM exerts cytoprotective effects. GCs upregulated the RIPK1 ubiquitinating factor BIRC3 (cIAP2), in GC-sensitive (CEM-C7-14) but not in resistant (CEM-C1-15) cells. In addition, CM selectively affected GR phosphorylation in a site and cell-specific manner. GR is recruited to RIPK1, BECN1 and BIRC3 promoters in the sensitive but not in the resistant cells with phosphorylated GR forms being generally less recruited in the presence of hormone. FACS analysis and caspase-8 assays demonstrated that CM promoted a pro-survival trend. High molecular weight proteins reacting with the RIPK1 antibody were modified upon incubation with the BIRC3 inhibitor AT406 in CEM-C7-14 cells suggesting that they represent ubiquitinated forms of RIPK1. Our data suggest that there is a correlation between microenvironment-induced ALL proliferation and altered response to chemotherapy. Public Library of Science 2017-06-05 /pmc/articles/PMC5459454/ /pubmed/28582465 http://dx.doi.org/10.1371/journal.pone.0178606 Text en © 2017 Qattan et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Qattan, Malak Yahia
Bakker, Emyr Yosef
Rajendran, Ramkumar
Chen, Daphne Wei-Chen
Saha, Vaskar
Liu, Jizhong
Zeef, Leo
Schwartz, Jean-Marc
Mutti, Luciano
Demonacos, Constantinos
Krstic-Demonacos, Marija
Differential regulation of cell death pathways by the microenvironment correlates with chemoresistance and survival in leukaemia
title Differential regulation of cell death pathways by the microenvironment correlates with chemoresistance and survival in leukaemia
title_full Differential regulation of cell death pathways by the microenvironment correlates with chemoresistance and survival in leukaemia
title_fullStr Differential regulation of cell death pathways by the microenvironment correlates with chemoresistance and survival in leukaemia
title_full_unstemmed Differential regulation of cell death pathways by the microenvironment correlates with chemoresistance and survival in leukaemia
title_short Differential regulation of cell death pathways by the microenvironment correlates with chemoresistance and survival in leukaemia
title_sort differential regulation of cell death pathways by the microenvironment correlates with chemoresistance and survival in leukaemia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5459454/
https://www.ncbi.nlm.nih.gov/pubmed/28582465
http://dx.doi.org/10.1371/journal.pone.0178606
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