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

Qattan, MY; Bakker, EY; Rajendran, R; Wei-Chen Chen, D; Saha, V; Liu, J; Schwartz, J; Mutti, L; Demonacos, C; Krstic- Demonacos, M

Authors

MY Qattan

EY Bakker

R Rajendran

D Wei-Chen Chen

V Saha

J Liu

J Schwartz

L Mutti

C Demonacos



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 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.

Citation

Qattan, M., Bakker, E., Rajendran, R., Wei-Chen Chen, D., Saha, V., Liu, J., …Krstic- Demonacos, M. (2017). Differential regulation of cell death pathways by the microenvironment correlates with chemoresistance and survival in leukaemia. PLoS ONE, 12(6), e0178606. https://doi.org/10.1371/journal.pone.0178606

Journal Article Type Article
Acceptance Date May 26, 2017
Online Publication Date Jun 5, 2017
Publication Date Jun 5, 2017
Deposit Date May 31, 2017
Publicly Available Date Jul 11, 2017
Journal PLoS ONE
Publisher Public Library of Science
Volume 12
Issue 6
Pages e0178606
DOI https://doi.org/10.1371/journal.pone.0178606
Publisher URL http://dx.doi.org/10.1371/journal.pone.0178606
Related Public URLs http://journals.plos.org/plosone/

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