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

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 TALL cell growth. Unexpectedly, MEK inhibitors (MEKi) enhanced growth of 70% of human TALL cell samples cultured on stromal cells independently of NOTCH activation and maintained their ability to propagate in vivo. Similar results were obtained when TALL 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 TALL growth in vitro, whereas the loss of function of IL-18 receptor in TALL 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 TALL -xeno-grafted mice and also in TALL 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 TALL development.
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Benjamin Uzan, Sandrine Poglio, Bastien Gerby, Ching‐lien Wu, Julia Gross, et al.. Interleukin‐18 produced by bone marrow‐derived stromal cells supports T ‐cell acute leukaemia progression. EMBO Molecular Medicine, Wiley Open Access, 2014, 6 (6), pp.821-834. ⟨10.1002/emmm.201303286⟩. ⟨hal-02353722⟩

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