C/EBPα regulated microRNA-34a targets E2F3 during granulopoiesis and is down-regulated in AML with CEBPA mutations

• Published in: Blood 2010-12, Vol.116 (25), p.5638-5649
• Main Authors: Pulikkan, John A., Peramangalam, Philomina S., Dengler, Viola, Ho, Phoenix A., Preudhomme, Claude, Meshinchi, Soheil, Christopeit, Maximilian, Nibourel, Oliver, Müller-Tidow, Carsten, Bohlander, Stefan K., Tenen, Daniel G., Behre, Gerhard
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Blotting, Western; CCAAT-Enhancer-Binding Proteins - genetics; CCAAT-Enhancer-Binding Proteins - metabolism; Cell Cycle; Cell Differentiation; Chromatin Immunoprecipitation; E2F1 Transcription Factor - genetics; E2F1 Transcription Factor - metabolism; E2F3 Transcription Factor - genetics; E2F3 Transcription Factor - metabolism; Flow Cytometry; Gene Expression Regulation, Neoplastic; Granulocytes - cytology; Hematologic and hematopoietic diseases; Hematopoietic Stem Cells - metabolism; Humans; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Leukopoiesis; Luciferases - metabolism; Medical sciences; MicroRNAs - physiology; Mutation - genetics; Myeloid Neoplasia; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Tumor Cells, Cultured
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2010-04-281600

The transcription factor, CCAAT enhancer binding protein alpha (C/EBPα), is crucial for granulopoiesis and is deregulated by various mechanisms in acute myeloid leukemia (AML). Mutations in the CEBPA gene are reported in 10% of human patients with AML. Even though the C/EBPα mutants are known to display distinct biologic function during leukemogenesis, the molecular basis for this subtype of AML remains elusive. We have recently showed the significance of deregulation of C/EBPα-regulated microRNA (miR) in AML. In this study, we report that miR-34a is a novel target of C/EBPα in granulopoiesis. During granulopoiesis, miR-34a targets E2F3 and blocks myeloid cell proliferation. Analysis of AML samples with CEBPA mutations revealed a lower expression of miR-34a and elevated levels of E2F3 as well as E2F1, a transcriptional target of E2F3. Manipulation of miR-34a reprograms granulocytic differentiation of AML blast cells with CEBPA mutations. These results define miR-34a as a novel therapeutic target in AML with CEBPA mutations.