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

Research output: Contribution to journalArticle

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

Bibliographical metadata

Original languageEnglish
Article numberPONE-D-17-09893R1
Pages (from-to)e0178606
Number of pages19
JournalPLoS ONE
Volume12
Issue number6
DOIs
StatePublished - 5 Jun 2017