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Transcriptional control and signal transduction, cell cycle

Aberrant expression of miR-9/9* in myeloid progenitors inhibits neutrophil differentiation by post-transcriptional regulation of ERG

Leukemia volume 30, pages 229–237 (2016)Cite this article

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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.

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Acknowledgements

This study was supported in part by an Erasmus MC grant (to MJL), Dutch Cancer Society grant (EMCR2009-4472 to MJL) and the Deutsche Forschungsgemeinschaft (SFB 1074 project B03 to LB). LB was supported in part by the Deutsche Forschungsgemeinschaft (Heisenberg-Stipendium BU 1339/3-1). We thank Dr VHJ van der Velden for help with flow cytometric analysis, Dr PJM Valk for providing the Dutch AML data set and critical revision of the manuscript and Professor Dr HR Delwel for his mentorship and contribution to interpretation of the data.

Author contributions

KN and SMS planned, carried out the experiments and analyzed the data. LB and HD provided the German data set and carried out experiments. KvL performed morphological evaluation and quantification of cytospins. SJE, CE and MKD performed experiments. EMJB, SJE, HD, LB, BL and MJL designed the study and interpreted the results. KN, SMS, SJE, LB, HD, BL and MJL wrote or contributed to the manuscript.

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  1. K Nowek and S M Sun: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands

    K Nowek, S M Sun, E M J Bindels, C Exalto, M K Dijkstra, K van Lom, S J Erkeland, B Löwenberg & M Jongen-Lavrencic

  2. Department of Internal Medicine III, University of Ulm, Ulm, Germany

    L Bullinger & H Döhner

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Correspondence to M Jongen-Lavrencic.

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Nowek, K., Sun, S., Bullinger, L. et al. Aberrant expression of miR-9/9* in myeloid progenitors inhibits neutrophil differentiation by post-transcriptional regulation of ERG. Leukemia 30, 229–237 (2016). https://doi.org/10.1038/leu.2015.183

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