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

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

Edité par CCSD ; Wiley Open Access -

International audience. Development 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.

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