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miR-139-5p controls translation in myeloid leukemia through EIF4G2

Emmrich, S
Author Emmrich, S Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
Engeland, F
Author Engeland, F Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
El-Khatib, M
Author El-Khatib, M Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
Henke, K
Author Henke, K Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
Obulkasim, A
Author Obulkasim, A Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands
Schöning, J
Author Schöning, J Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
Katsman-Kuipers, J E
Author Katsman-Kuipers, J E Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands
Michel Zwaan, C
Author Michel Zwaan, C Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands
Pich, A
Author Pich, A Institute for Toxicology, Hannover Medical School, Hannover, Germany
Stary, J
Author Stary, J Department of Pediatric Hematology/Oncology, Charles University and University Hospital Motol, Prague, Czech Republic
Baruchel, A
Author Baruchel, A Department of Hematology, Hopitaux universitaires Saint-Louis, St Louis Hospital, Paris, France
de Haas, V
Author de Haas, V Dutch Childhood Oncology Group (DCOG), Stichting Kinderoncologie Nederland (SKION), Hague, The Netherlands
Reinhardt, D
Author Reinhardt, D Clinic for Pediatrics III, University Hospital Essen, Essen, Germany
Fornerod, M
Author Fornerod, M Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands Department of Biochemistry, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands
van den Heuvel-Eibrink, M M
Author van den Heuvel-Eibrink, M M Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands
Klusmann, J H
Author Klusmann, J H Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany

Oncogene. 2016 Apr 07 ; 35 (14) : 1822-31. [epub] 20150713

ISSN 1476-5594 | 0950-9232
Source

Language English Country England, Great Britain Media print-electronic

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link https://www.medvik.cz/link/pmid26165837

PubMed 26165837
DOI 10.1038/onc.2015.247
PII: onc2015247
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
Names of Substances
EIF4G2 protein, human MeSH Browser
Eukaryotic Initiation Factor-4G MeSH
MicroRNAs MeSH
MIRN139 microRNA, human MeSH Browser

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 Biochemistry Erasmus MC Sophia Children's Hospital Rotterdam The Netherlands

Department of Hematology Hopitaux universitaires Saint Louis St Louis Hospital Paris France

Department of Pediatric Hematology and Oncology Hannover Medical School Hannover Germany

Department of Pediatric Hematology Oncology Charles University and University Hospital Motol Prague Czech Republic

Department of Pediatric Oncology Hematology Erasmus MC Sophia Children's Hospital Rotterdam The Netherlands

Dutch Childhood Oncology Group Hague The Netherlands

Institute for Toxicology Hannover Medical School Hannover Germany

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