title: Aberrant expression of miR-9/9* in myeloid progenitors inhibits neutrophil differentiation by post-transcriptional regulation of ERG.
abstract: Aberrant post-transcriptional regulation by microRNAs (miRNAs) has been shown to be involved in the pathogenesis of acute myeloid leukemia (AML). In a previous study, we performed a large functional screen using a retroviral barcoded miRNA expression library. Here, we report that overexpression of miR-9/9* in myeloid 32D cell line (32D-miR-9/9*) had profound impact on granulocyte colony-stimulating factor-induced differentiation. Further in vitro studies showed that enforced expression of miR-9/9* blocked normal neutrophil development in 32D and in primary murine lineage-negative bone marrow cells. We examined the expression of miR-9/9* in a cohort of 647 primary human AMLs. In most cases, miR-9 and miR-9* were significantly upregulated and their expression levels varied according to AML subtype, with the highest expression in MLL-related leukemias harboring 11q23 abnormalities and the lowest expression in AML cases with t(8;21) and biallelic mutations in CEBPA. Gene expression profiling of AMLs with high expression of miR-9/9* and 32D-miR-9/9* identified ETS-related gene (Erg) as the only common potential target. Upregulation of ERG in 32D cells rescued miR-9/9*-induced block in neutrophil differentiation. Taken together, this study demonstrates that miR-9/9* are aberrantly expressed in most of AML cases and interfere with normal neutrophil differentiation by downregulation of ERG.
authors.affiliation: Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Nowek
authors.affiliation: Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands.
authors.forename: S M
authors.initials: SM
authors.lastname: Sun
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Bullinger
authors.affiliation: Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands.
authors.forename: E M J
authors.initials: EM
authors.lastname: Bindels
authors.affiliation: Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Exalto
authors.affiliation: Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands.
authors.forename: M K
authors.initials: MK
authors.lastname: Dijkstra
authors.affiliation: Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: van Lom
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Döhner
authors.affiliation: Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands.
authors.forename: S J
authors.initials: SJ
authors.lastname: Erkeland
authors.affiliation: Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Löwenberg
authors.affiliation: Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Jongen-Lavrencic
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D023461:Myeloid Progenitor Cells / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology*; D015534:Trans-Activators / Q000235:genetics*; D000071230:Transcriptional Regulator ERG
chemical_list: C072312:ERG protein, human; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG