1. Disruption of the C/EBPα-miR-182 balance impairs granulocytic differentiation.
- Author
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Wurm AA, Zjablovskaja P, Kardosova M, Gerloff D, Bräuer-Hartmann D, Katzerke C, Hartmann JU, Benoukraf T, Fricke S, Hilger N, Müller AM, Bill M, Schwind S, Tenen DG, Niederwieser D, Alberich-Jorda M, and Behre G
- Subjects
- Animals, Blotting, Western, CCAAT-Enhancer-Binding Proteins metabolism, Cell Differentiation genetics, Humans, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute mortality, Mice, Mice, Knockout, MicroRNAs metabolism, Prognosis, Real-Time Polymerase Chain Reaction, CCAAT-Enhancer-Binding Proteins genetics, Granulocytes, Leukemia, Myeloid, Acute genetics, Leukopoiesis genetics, MicroRNAs genetics
- 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.C/EBPα is a critical transcription factor involved in myelopoiesis and its inactivation is associated with acute myeloid leukemia (AML). Here the authors show a negative feedback loop between C/EBPα and miR-182 and identify this miRNA as a marker of high-risk AML.
- Published
- 2017
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