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Article Dans Une Revue EMBO Molecular Medicine Année : 2014

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

Bastien Gerby
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Xavier Cahu
  • Fonction : Auteur
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Caroline Deswarte
Florent Dumont
Véronique Baud

Résumé

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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Dates et versions

hal-01085028 , version 1 (20-11-2014)

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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, 2014, 6 (6), pp.821 - 834. ⟨10.1002/emmm.201303286⟩. ⟨hal-01085028⟩
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