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Interleukin-18 produced by bone marrow- derived stromal cells supports T-cell acute leukaemia progression

By 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, André Baruchel, Judith Landman-Parker, Paola Ballerini, Véronique Baud, Jacques Ghysdael, Frédéric Baleydier, Francoise Porteu and Francoise Pflumio

Abstract

International audienceDevelopment of novel therapies is critical for T-cell acute leukae-mia (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 activa-tion 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 interleu-kin 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-xeno-grafted 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

Topics: IL-18, inflammation, stromal cells, T-ALL Subject Categories Cancer, Haematology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
Publisher: 'Wiley'
Year: 2014
DOI identifier: 10.1002/emmm.201303286
OAI identifier: oai:HAL:hal-01085028v1
Provided by: HAL-HCL
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