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Interleukin‐18 produced by bone marrow‐derived stromal cells supports T ‐cell acute leukaemia progression
- Source :
- EMBO Molecular Medicine, EMBO Molecular Medicine, Wiley Open Access, 2014, 6 (6), pp.821-834. ⟨10.1002/emmm.201303286⟩, EMBO Molecular Medicine, 2014, 6 (6), pp.821-834. ⟨10.1002/emmm.201303286⟩, EMBO Molecular Medicine, Wiley Open Access, 2014, 6, pp.821-834. 〈10.1002/emmm.201303286〉
- Publication Year :
- 2014
- Publisher :
- HAL CCSD, 2014.
-
Abstract
- International audience; 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.
- Subjects :
- MAPK/ERK pathway
Stromal cell
MAP Kinase Signaling System
T-Lymphocytes
medicine.medical_treatment
T cell
[SDV]Life Sciences [q-bio]
Bone Marrow Cells
[SDV.CAN]Life Sciences [q-bio]/Cancer
Biology
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Cell Line
Mice
03 medical and health sciences
0302 clinical medicine
Mice, Inbred NOD
Cell Line, Tumor
medicine
[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology
Animals
Humans
[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
Gene Silencing
[ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology
Research Articles
ComputingMilieux_MISCELLANEOUS
Cell Proliferation
030304 developmental biology
stromal cells
0303 health sciences
Gene Expression Regulation, Leukemic
Cell growth
Interleukin-18
T-ALL Subject Categories Cancer
Cytokine
medicine.anatomical_structure
Cell culture
inflammation
030220 oncology & carcinogenesis
Immunology
Cancer research
Molecular Medicine
Interleukin 18
Bone marrow
T-ALL
IL-18
Haematology
Subjects
Details
- Language :
- English
- ISSN :
- 17574676 and 17574684
- Database :
- OpenAIRE
- Journal :
- EMBO Molecular Medicine, EMBO Molecular Medicine, Wiley Open Access, 2014, 6 (6), pp.821-834. ⟨10.1002/emmm.201303286⟩, EMBO Molecular Medicine, 2014, 6 (6), pp.821-834. ⟨10.1002/emmm.201303286⟩, EMBO Molecular Medicine, Wiley Open Access, 2014, 6, pp.821-834. 〈10.1002/emmm.201303286〉
- Accession number :
- edsair.doi.dedup.....650e12c8f0328b1751eb0c26258408f7