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C/EBPα regulated microRNA-34a targets E2F3 during granulopoiesis and is down-regulated in AML with CEBPA mutations. Blood 2010 Dec 16;116(25):5638-49 PMID: 20889924 PMCID: PMC3031410

Pubmed ID

20889924

DOI

10.1182/blood-2010-04-281600

Abstract

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.

Author List

Pulikkan JA, Peramangalam PS, Dengler V, Ho PA, Preudhomme C, Meshinchi S, Christopeit M, Nibourel O, Müller-Tidow C, Bohlander SK, Tenen DG, Behre G

Author

John A. Pulikkan PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin




Scopus

2-s2.0-78650459322   93 Citations

MESH terms used to index this publication - Major topics in bold

Blotting, Western
CCAAT-Enhancer-Binding Proteins
Cell Cycle
Cell Differentiation
Chromatin Immunoprecipitation
E2F1 Transcription Factor
E2F3 Transcription Factor
Flow Cytometry
Gene Expression Regulation, Neoplastic
Granulocytes
Hematopoietic Stem Cells
Humans
Leukemia, Myeloid, Acute
Leukopoiesis
Luciferases
MicroRNAs
Mutation
RNA, Messenger
Reverse Transcriptase Polymerase Chain Reaction
Tumor Cells, Cultured
jenkins-FCD Prod-353 9ccd8489072cb19f5b9f808bb23ed672c582f41e