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miR-139-5p controls translation in myeloid leukemia through EIF4G2
S. Emmrich, F. Engeland, M. El-Khatib, K. Henke, A. Obulkasim, J. Schöning, JE. Katsman-Kuipers, C. Michel Zwaan, A. Pich, J. Stary, A. Baruchel, V. de Haas, D. Reinhardt, M. Fornerod, MM. van den Heuvel-Eibrink, JH. Klusmann,
Language English Country England, Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't
NLK
ProQuest Central
from 2000-01-01 to 1 year ago
Open Access Digital Library
from 1997-01-01
Health & Medicine (ProQuest)
from 2000-01-01 to 1 year ago
Public Health Database (ProQuest)
from 2000-01-01 to 1 year ago
PubMed
26165837
DOI
10.1038/onc.2015.247
Knihovny.cz E-resources
- MeSH
- Cell Differentiation genetics MeSH
- Eukaryotic Initiation Factor-4G biosynthesis genetics MeSH
- Gene Knockdown Techniques MeSH
- Humans MeSH
- MicroRNAs biosynthesis genetics MeSH
- Leukemia, Myeloid genetics pathology MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Cell Proliferation genetics MeSH
- Protein Biosynthesis * MeSH
- Gene Expression Regulation, Leukemic MeSH
- Xenograft Model Antitumor Assays MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
MicroRNAs (miRNAs) are crucial components of homeostatic and developmental gene regulation. In turn, dysregulation of miRNA expression is a common feature of different types of cancer, which can be harnessed therapeutically. Here we identify miR-139-5p suppression across several cytogenetically defined acute myeloid leukemia (AML) subgroups. The promoter of mir-139 was transcriptionally silenced and could be reactivated by histone deacetylase inhibitors in a dose-dependent manner. Restoration of mir-139 expression in cell lines representing the major AML subgroups (t[8;21], inv[16], mixed lineage leukemia-rearranged and complex karyotype AML) caused cell cycle arrest and apoptosis in vitro and in xenograft mouse models in vivo. During normal hematopoiesis, mir-139 is exclusively expressed in terminally differentiated neutrophils and macrophages. Ectopic expression of mir-139 repressed proliferation of normal CD34(+)-hematopoietic stem and progenitor cells and perturbed myelomonocytic in vitro differentiation. Mechanistically, mir-139 exerts its effects by repressing the translation initiation factor EIF4G2, thereby reducing overall protein synthesis while specifically inducing the translation of cell cycle inhibitor p27(Kip1). Knockdown of EIF4G2 recapitulated the effects of mir-139, whereas restoring EIF4G2 expression rescued the mir-139 phenotype. Moreover, elevated miR-139-5p expression is associated with a favorable outcome in a cohort of 165 pediatric patients with AML. Thus, mir-139 acts as a global tumor suppressor-miR in AML by controlling protein translation. As AML cells are dependent on high protein synthesis rates controlling the expression of mir-139 constitutes a novel path for the treatment of AML.
Clinic for Pediatrics 3 University Hospital Essen Essen Germany
Department of Hematology Hopitaux universitaires Saint Louis St Louis Hospital Paris France
Department of Pediatric Hematology and Oncology Hannover Medical School Hannover Germany
Dutch Childhood Oncology Group Hague The Netherlands
Institute for Toxicology Hannover Medical School Hannover Germany
References provided by Crossref.org
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