Interleukin‐18 produced by bone marrow‐derived stromal cells supports T‐cell acute leukaemia progression
Open Access
- 28 April 2014
- journal article
- research article
- Published by Springer Science and Business Media LLC in EMBO Molecular Medicine
- Vol. 6 (6), 821-834
- https://doi.org/10.1002/emmm.201303286
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. Synopsis Chemical inhibition of MEK induces growth of human T‐cell acute leukaemia (T‐ALL) cells via the release of pro‐inflammatory IL‐18 by bone marrow‐derived stromal cells in the tumour microenvironment. MEK chemical inhibitors induce growth of T‐ALL patient samples during co‐cultures with stromal cells. Growth induced by MEK inhibitors are related to the release of IL‐18 pro‐inflammatory cytokine by bone marrow‐derived stromal cells. Functional experiments in vitro and in vivo pinpoint IL‐18 as a T‐ALL growth factor. Plasmatic IL‐18 levels are enhanced in mouse models as well as in human T‐ALL patients. Bone marrow‐secreted factors contribute to human T‐ALL.Keywords
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