학술논문
Interleukin‐18 produced by bone marrow‐derived stromal cells supports T‐cell acute leukaemia progression
Document Type
article
Author
Benjamin Uzan; Sandrine Poglio; Bastien Gerby; Ching‐Lien Wu; Julia Gross; Florence Armstrong; Julien Calvo; Xavier Cahu; Caroline Deswarte; Florent Dumont; Diana Passaro; Corinne Besnard‐Guérin; Thierry Leblanc; André Baruchel; Judith Landman‐Parker; Paola Ballerini; Véronique Baud; Jacques Ghysdael; Frédéric Baleydier; Francoise Porteu; Francoise Pflumio
Source
EMBO Molecular Medicine, Vol 6, Iss 6, Pp 821-834 (2014)
Subject
Language
English
ISSN
1757-4684
1757-4676
1757-4676
Abstract
Abstract 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 in vivo. Similar results were obtained when T‐ALL cells were cultured with ERK1/2‐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 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.