Interleukin‐18 produced by bone marrow‐derived stromal cells supports T‐cell acute leukaemia progression. Issue 6 (28th April 2014)

• Record Type: Journal Article
• Authors: Uzan, Benjamin; Poglio, Sandrine; Gerby, Bastien; Wu, Ching‐Lien; Gross, Julia; Armstrong, Florence; Calvo, Julien; Cahu, Xavier; Deswarte, Caroline; Dumont, Florent; Passaro, Diana; Besnard‐Guérin, Corinne; Leblanc, Thierry; Baruchel, André; Landman‐Parker, Judith; Ballerini, Paola; Baud, Véronique; Ghysdael, Jacques; Baleydier, Frédéric; Porteu, Francoise; Pflumio, Francoise
• Is Part Of: EMBO molecular medicine. Volume 6:Issue 6(2014:Jun.)
• Page Start: 821
• Page End: 834
• Publication Date: 2014-04-28
• Subjects: Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.1002/emmm.201303286
• Languages: English
• ISSNs: 1757-4676

Abstract

<abstract abstract-type="main" id="emmm201303286-abs-0001"> <title>Abstract</title> <p>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 (MEKi) enhanced growth of 70% of human T‐ALL cell samples cultured on stromal cells independently of NOTCH activation and maintained their ability to propagate <italic>in vivo</italic>. Similar results were obtained when T‐ALL cells were cultured with <italic>ERK1/2</italic>‐knockdown stromal cells or with conditioned medium from MEKi‐treated stromal cells. Microarray analysis identified interleukin 18 (IL‐18) as transcriptionally up‐regulated in MEKi‐treated MS5 cells. Recombinant IL‐18 promoted T‐ALL growth <italic>in vitro</italic>, whereas the loss of function of IL‐18 receptor in T‐ALL blast cells decreased blast proliferation <italic>in vitro</italic> 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.</p> </abstract>