C/EBPα regulated microRNA-34a targets E2F3 during granulopoiesis and is down-regulated in AML with CEBPA mutations.
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.
Pulikkan
John A
JA
Department of Internal Medicine IV-Oncology and Hematology, Martin Luther University Halle-Wittenberg, Halle, Germany
Peramangalam
Philomina S
PS
Dengler
Viola
V
Ho
Phoenix A
PA
Preudhomme
Claude
C
Meshinchi
Soheil
S
Christopeit
Maximilian
M
Nibourel
Oliver
O
Müller-Tidow
Carsten
C
Bohlander
Stefan K
SK
Tenen
Daniel G
DG
Behre
Gerhard
G
D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D002454:Cell Differentiation; D047369:Chromatin Immunoprecipitation; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050699:E2F3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006098:Granulocytes / Q000166:cytology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019891:Leukopoiesis; D008156:Luciferases / Q000378:metabolism; D035683:MicroRNAs / Q000502:physiology*; D009154:Mutation / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D050699:E2F3 Transcription Factor; C098319:E2F3 protein, human; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D008156:Luciferases