TY - JOUR
T1 - Interleukin-18 produced by bone marrow-derived stromal cells supports T-cell acute leukaemia progression
AU - Uzan, Benjamin
AU - Poglio, Sandrine
AU - Gerby, Bastien
AU - Wu, Ching Lien
AU - Gross, Julia
AU - Armstrong, Florence
AU - Calvo, Julien
AU - Cahu, Xavier
AU - Deswarte, Caroline
AU - Dumont, Florent
AU - Passaro, Diana
AU - Besnard-Guérin, Corinne
AU - Leblanc, Thierry
AU - Baruchel, André
AU - Landman-Parker, Judith
AU - Ballerini, Paola
AU - Baud, Véronique
AU - Ghysdael, Jacques
AU - Baleydier, Frédéric
AU - Porteu, Francoise
AU - Pflumio, Francoise
PY - 2014/1/1
Y1 - 2014/1/1
N2 - 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. 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.
AB - 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. 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.
KW - IL-18
KW - Inflammation
KW - Stromal cells
KW - T-ALL
UR - http://www.scopus.com/inward/record.url?scp=84901831232&partnerID=8YFLogxK
U2 - 10.1002/emmm.201303286
DO - 10.1002/emmm.201303286
M3 - Article
C2 - 24778454
AN - SCOPUS:84901831232
SN - 1757-4676
VL - 6
SP - 821
EP - 834
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 6
ER -