title: miR-139-5p controls translation in myeloid leukemia through EIF4G2.
abstract: 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.
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Emmrich
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Engeland
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: El-Khatib
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Henke
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Obulkasim
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Schöning
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: J E
authors.initials: JE
authors.lastname: Katsman-Kuipers
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Michel Zwaan
authors.affiliation: Institute for Toxicology, Hannover Medical School, Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Pich
authors.affiliation: Department of Pediatric Hematology/Oncology, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Stary
authors.affiliation: Department of Hematology, Hopitaux universitaires Saint-Louis, St Louis Hospital, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Baruchel
authors.affiliation: Dutch Childhood Oncology Group (DCOG), Stichting Kinderoncologie Nederland (SKION), Hague, The Netherlands.
authors.forename: V
authors.initials: V
authors.lastname: de Haas
authors.affiliation: Clinic for Pediatrics III, University Hospital Essen, Essen, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Reinhardt
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Fornerod
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: M M
authors.initials: MM
authors.lastname: van den Heuvel-Eibrink
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: J H
authors.initials: JH
authors.lastname: Klusmann
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D039603:Eukaryotic Initiation Factor-4G / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D055785:Gene Knockdown Techniques; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D014176:Protein Biosynthesis; D023041:Xenograft Model Antitumor Assays
chemical_list: C491300:EIF4G2 protein, human; D039603:Eukaryotic Initiation Factor-4G; C555098:MIRN139 microRNA, human; D035683:MicroRNAs