AML1−ETO downregulates the granulocytic differentiation factor C/EBP in t(8;21) myeloid leukemia
Thomas Pabst1, Beatrice U. Mueller1, Nari Harakawa1, Claudia Schoch2, Torsten Haferlach2, Gerhard Behre2, Wolfgang Hiddemann2, Dong-Er Zhang3
& Daniel G. Tenen1
1
Hematology/Oncology Division, Harvard Institutes of Medicine, Harvard Medical School, Boston, Massachusetts, USA
2
Department of Medicine III, Grosshadern, and Clinical Cooperative Group Acute Myeloid Leukemia of the National Research Center for Environment and Health (GSF), Munich, Germany
3
The Scripps Research Institute, La Jolla, California, USA
The transcription factor CCAAT/enhancer binding protein , or C/EBP, encoded by the CEBPA gene, is crucial for the differentiation of granulocytes. Conditional expression of C/EBP 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 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 expression indirectly by inhibiting positive autoregulation of the CEBPA promoter. Conditional expression of C/EBP in AML1−ETO-positive Kasumi-1 cells results in neutrophilic differentiation. We suggest that restoring C/EBP expression will have therapeutic implications in RUNX1−CBF2T1-positive leukemias.
in t(8;21) myeloid leukemia
, or C/EBP
