Open AccessInterleukin‐18 produced by bone marrow‐derived stromal cells supports T ‐cell acute leukaemia progression
Author(s) -
Uzan Benjamin,
Poglio Sandrine,
Gerby Bastien,
Wu ChingLien,
Gross Julia,
Armstrong Florence,
Calvo Julien,
Cahu Xavier,
Deswarte Caroline,
Dumont Florent,
Passaro Diana,
BesnardGuérin Corinne,
Leblanc Thierry,
Baruchel André,
LandmanParker Judith,
Ballerini Paola,
Baud Véronique,
Ghysdael Jacques,
Baleydier Frédéric,
Porteu Francoise,
Pflumio Francoise
Publication year - 2014
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201303286
Subject(s) - stromal cell , bone marrow , cancer research , mapk/erk pathway , cytokine , cell growth , t cell , chemistry , biology , microbiology and biotechnology , immunology , signal transduction , immune system , biochemistry
Development of novel therapies is critical for T ‐cell acute leukaemia ( T ‐ ALL ). Here, we investigated the effect of inhibiting the MAPK / MEK / ERK pathway on T ‐ ALL cell growth. Unexpectedly, MEK inhibitors ( MEK i) enhanced growth of 70% of human T ‐ ALL cell samples cultured on stromal cells independently of NOTCH activation and maintained their ability to propagate in vivo . Similar results were obtained when T‐ ALL cells were cultured with ERK1/2 ‐knockdown stromal cells or with conditioned medium from MEK i‐treated stromal cells. Microarray analysis identified interleukin 18 ( IL ‐18) as transcriptionally up‐regulated in MEK i‐treated MS 5 cells. Recombinant IL ‐18 promoted T‐ ALL growth in vitro , whereas the loss of function of IL ‐18 receptor in T‐ ALL blast cells decreased blast proliferation in vitro and in NSG mice. The NFKB pathway that is downstream to IL ‐18R was activated by IL ‐18 in blast cells. IL ‐18 circulating levels were increased in T ‐ ALL ‐xenografted mice and also in T ‐ ALL patients in comparison with controls. This study uncovers a novel role of the pro‐inflammatory cytokine IL ‐18 and outlines the microenvironment involvement in human T ‐ ALL development.