CCAAT/enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors.
The transcription factor CCAAT/enhancer binding protein alpha (C/EBPalpha) regulates a number of myeloid cell-specific genes. To delineate the role of C/EBPalpha in human granulopoiesis, we studied its expression and function in human primary cells and bipotential (granulocytic/monocytic) myeloid cell lines. We show that the expression of C/EBPalpha initiates with the commitment of multipotential precursors to the myeloid lineage, is specifically upregulated during granulocytic differentiation, and is rapidly downregulated during the alternative monocytic pathway. Conditional expression of C/EBPalpha alone in stably transfected bipotential cells triggers neutrophilic differentiation, concomitant with upregulation of the granulocyte-specific granulocyte colony-stimulating factor receptor and secondary granule protein genes. Moreover, induced expression of C/EBPalpha in bipotential precursors blocks their monocytic differentiation program. These results indicate that C/EBPalpha serves as a myeloid differentiation switch acting on bipotential precursors and directing them to mature to granulocytes.
Radomska
H S
HS
Hematology/Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Huettner
C S
CS
Zhang
P
P
Cheng
T
T
Scadden
D T
DT
Tenen
D G
DG
D022762:CCAAT-Enhancer-Binding Proteins; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D015870:Gene Expression; D006098:Granulocytes / Q000166:cytology*; D018922:HL-60 Cells; D006367:HeLa Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D009000:Monocytes / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D013755:Tetradecanoylphorbol Acetate