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

  • External authors:
  • Malak Yahia Qattan
  • Emyr Yosef Bakker
  • Ramkumar Rajendran
  • Daphne Wei-Chen Chen
  • Jizhong Liu
  • Leo Zeef
  • Luciano Mutti
  • Marija Krstic-Demonacos

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Differential regulation of cell death pathways by the microenvironment correlates with chemoresistance and survival in leukaemia : The role of microenvironment in ALL chemoresistance. / 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.

In: PLoS ONE, Vol. 12, No. 6, PONE-D-17-09893R1, 05.06.2017, p. e0178606.

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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 : The role of microenvironment in ALL chemoresistance. In: PLoS ONE. 2017 ; Vol. 12, No. 6. pp. e0178606.

Bibtex

@article{5ce6d7800a204d5ba42c132c1c5cd596,
title = "Differential regulation of cell death pathways by the microenvironment correlates with chemoresistance and survival in leukaemia: The role of microenvironment in ALL chemoresistance",
abstract = "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 cell pro-survival trend. High molecular weight proteins reacting with the RIPK1 antibody increased in the presence of CM and were reduced upon incubation with the BIRC3 inhibitor AT406 in C7 cells suggesting that they represent ubiquitinated forms of RIPK1. Our data suggest that the bone marrow microenvironment facilitates ALL proliferation leading to altered response to the treatment with different chemotherapeutics.",
keywords = "glucocorticoid receptor , gene expression, microenvironment, Acute Lymphoblastic Leukemia, cancer , Cell Death",
author = "Qattan, {Malak Yahia} and Bakker, {Emyr Yosef} and Ramkumar Rajendran and Chen, {Daphne Wei-Chen} and Vaskar Saha and Jizhong Liu and Leo Zeef and Jean-Marc Schwartz and Luciano Mutti and Constantinos Demonacos and Marija Krstic-Demonacos",
year = "2017",
month = "6",
day = "5",
doi = "10.1371/journal.pone.0178606",
language = "English",
volume = "12",
pages = "e0178606",
journal = "P L o S One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "6",

}

RIS

TY - JOUR

T1 - Differential regulation of cell death pathways by the microenvironment correlates with chemoresistance and survival in leukaemia

T2 - The role of microenvironment in ALL chemoresistance

AU - Qattan, Malak Yahia

AU - Bakker, Emyr Yosef

AU - Rajendran, Ramkumar

AU - Chen, Daphne Wei-Chen

AU - Saha, Vaskar

AU - Liu, Jizhong

AU - Zeef, Leo

AU - Schwartz, Jean-Marc

AU - Mutti, Luciano

AU - Demonacos, Constantinos

AU - Krstic-Demonacos, Marija

PY - 2017/6/5

Y1 - 2017/6/5

N2 - 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 cell pro-survival trend. High molecular weight proteins reacting with the RIPK1 antibody increased in the presence of CM and were reduced upon incubation with the BIRC3 inhibitor AT406 in C7 cells suggesting that they represent ubiquitinated forms of RIPK1. Our data suggest that the bone marrow microenvironment facilitates ALL proliferation leading to altered response to the treatment with different chemotherapeutics.

AB - 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 cell pro-survival trend. High molecular weight proteins reacting with the RIPK1 antibody increased in the presence of CM and were reduced upon incubation with the BIRC3 inhibitor AT406 in C7 cells suggesting that they represent ubiquitinated forms of RIPK1. Our data suggest that the bone marrow microenvironment facilitates ALL proliferation leading to altered response to the treatment with different chemotherapeutics.

KW - glucocorticoid receptor

KW - gene expression

KW - microenvironment

KW - Acute Lymphoblastic Leukemia

KW - cancer

KW - Cell Death

U2 - 10.1371/journal.pone.0178606

DO - 10.1371/journal.pone.0178606

M3 - Article

VL - 12

SP - e0178606

JO - P L o S One

JF - P L o S One

SN - 1932-6203

IS - 6

M1 - PONE-D-17-09893R1

ER -