Oxidative stress as candidate therapeutic target to overcome microenvironmental protection of CLL.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
18
08
2017
accepted:
18
04
2019
revised:
15
01
2019
pubmed:
14
7
2019
medline:
2
7
2020
entrez:
14
7
2019
Statut:
ppublish
Résumé
Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental non-malignant cells for survival. We compared the transcriptomes of primary CLL cells cocultured or not with protective bone marrow stromal cells (BMSCs) and found that oxidative phosphorylation, mitochondrial function, and hypoxic signaling undergo most significant dysregulation in non-protected CLL cells, with the changes peaking at 6-8 h, directly before induction of apoptosis. A subset of CLL patients displayed a gene expression signature resembling that of cocultured CLL cells and had significantly worse progression-free and overall survival. To identify drugs blocking BMSC-mediated support, we compared the relevant transcriptomic changes to the Connectivity Map database. Correlation was found with the transcriptomic signatures of the cardiac glycoside ouabain and of the ipecac alkaloids emetine and cephaeline. These compounds were highly active against protected primary CLL cells (relative IC
Identifiants
pubmed: 31300746
doi: 10.1038/s41375-019-0513-x
pii: 10.1038/s41375-019-0513-x
doi:
Substances chimiques
Emetine
X8D5EPO80M
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
115-127Références
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