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

EMBO Molecular Medicine

Benjamin Uzan¹  Sandrine Poglio¹  Bastien Gerby¹  Ching-Lien Wu¹  Julia Gross¹  Florence Armstrong¹  Julien Calvo¹  Xavier Cahu¹  Caroline Deswarte³  Florent Dumont²  Diana Passaro⁴  Corinne Besnard-Guérin²  Thierry Leblanc⁵  André Baruchel⁵  Judith Landman-Parker³  Paola Ballerini¹  Véronique Baud²  Jacques Ghysdael⁴  Frédéric Baleydier⁶  Francoise Porteu² 

[1] Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), DSV-IRCM-SCSR-LSHL, Equipe Labellisée Ligue Contre le Cancer, UMR 967, Fontenay-aux-Roses, France;INSERM U1016, Institut Cochin, Paris, France;Service D'hématologie Pédiatrique, Assistance Publique – Hôpitaux de Paris, Hôpital A. Trousseau, Paris, France;Institut Curie, Centre Universitaire, Orsay, France;Service D'hématologie Pédiatrique, Assistance Publique – Hôpitaux de Paris, Hôpital Robert Debré, Paris, France;Institut d'Hématologie et Oncologie Pédiatrique, Hospices Civils de Lyon et Université Claude Bernard, Lyon, France

关键词: IL‐18;    inflammation;    stromal cells;    T‐ALL;   

DOI  :  10.1002/emmm.201303286

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.