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AML1-ETO downregulates the granulocytic differentiation factor C/EBP[alpha] in t(8;21) myeloid leukemia
- Source :
- Nature Medicine. April, 2001, Vol. 7 Issue 4, p444, 8 p.
- Publication Year :
- 2001
-
Abstract
- The transcription factor CCAAT/enhancer binding protein [alpha], or C/EBP[alpha], encoded by the CEBPA gene, is crucial for the differentiation of granulocytes. Conditional expression of C/EBP[alpha] triggers neutrophilic differentiation, and Cebpa knockout mice exhibit an early block in maturation. Dominant-negative mutations of CEBPA have been found in some patients with acute myeloid leukemia (AML), but not in AML with the t(8;21) translocation which gives rise to the fusion gene RUNX1-CBF2T1 (also known as AML1-ETO) encoding the AML1-ETO fusion protein. RUNX1-CBF2T1 positive-AML blasts had eight-fold lower CEBPA RNA levels and undetectable C/EBP[alpha] protein levels compared with other subgroups of AML patients. Conditional expression of RUNX1-CBF2T1 in U937 cells downregulated CEBPA mRNA, protein and DNA binding activity. AML1-ETO appears to suppress C/EBP[alpha] expression indirectly by inhibiting positive autoregulation of the CEBPA promoter. Conditional expression of C/EBP[alpha] in AML1-ETO-positive Kasumi-1 cells results in neutrophilic differentiation. We suggest that restoring C/EBP[alpha] expression will have therapeutic implications in RUNX1-CBF2T1-positive leukemias.<br />Author(s): Thomas Pabst [1]; Beatrice U. Mueller [1]; Nari Harakawa [1]; Claudia Schoch [2]; Torsten Haferlach [2]; Gerhard Behre [2]; Wolfgang Hiddemann [2]; Dong-Er Zhang [3]; Daniel G. Tenen (corresponding [...]
Details
- Language :
- English
- ISSN :
- 10788956
- Volume :
- 7
- Issue :
- 4
- Database :
- Gale General OneFile
- Journal :
- Nature Medicine
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.193842389
- Full Text :
- https://doi.org/10.1038/86515