Disruption of the C/EBPα—miR-182 balance impairs granulocytic differentiation

Alexander Arthur Wurm, Polina Zjablovskaja, Miroslava Kardosova, Dennis Gerloff, Daniela Bräuer-Hartmann, Christiane Katzerke, Jens-Uwe Hartmann, Touati Benoukraf, Stephan Fricke, Nadja Hilger, Anne-Marie Müller, Marius Bill, Sebastian Schwind, Daniel G. Tenen, Dietger Niederwieser, Meritxell Alberich-Jorda and Gerhard Behre ()
Additional contact information
Alexander Arthur Wurm: Leipzig University Hospital
Polina Zjablovskaja: Academy of Sciences of the Czech Republic
Miroslava Kardosova: Academy of Sciences of the Czech Republic
Dennis Gerloff: Leipzig University Hospital
Daniela Bräuer-Hartmann: Leipzig University Hospital
Christiane Katzerke: Leipzig University Hospital
Jens-Uwe Hartmann: Leipzig University Hospital
Touati Benoukraf: National University of Singapore
Stephan Fricke: Fraunhofer Institute for Cell Therapy and Immunology
Nadja Hilger: Fraunhofer Institute for Cell Therapy and Immunology
Anne-Marie Müller: Fraunhofer Institute for Cell Therapy and Immunology
Marius Bill: Leipzig University Hospital
Sebastian Schwind: Leipzig University Hospital
Daniel G. Tenen: National University of Singapore
Dietger Niederwieser: Leipzig University Hospital
Meritxell Alberich-Jorda: Academy of Sciences of the Czech Republic
Gerhard Behre: Leipzig University Hospital

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract Transcription factor C/EBPα is a master regulator of myelopoiesis and its inactivation is associated with acute myeloid leukemia. Deregulation of C/EBPα by microRNAs during granulopoiesis or acute myeloid leukemia development has not been studied. Here we show that oncogenic miR-182 is a strong regulator of C/EBPα. Moreover, we identify a regulatory loop between C/EBPα and miR-182. While C/EBPα blocks miR-182 expression by direct promoter binding during myeloid differentiation, enforced expression of miR-182 reduces C/EBPα protein level and impairs granulopoiesis in vitro and in vivo. In addition, miR-182 expression is highly elevated particularly in acute myeloid leukemia patients with C-terminal CEBPA mutations, thereby depicting a mechanism by which C/EBPα blocks miR-182 expression. Furthermore, we present miR-182 expression as a prognostic marker in cytogenetically high-risk acute myeloid leukemia patients. Our data demonstrate the importance of a controlled balance between C/EBPα and miR-182 for the maintenance of healthy granulopoiesis.

Date: 2017
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DOI: 10.1038/s41467-017-00032-6

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