AML1-ETO downregulates the granulocytic differentiation factor C/EBPα in t(8;21) myeloid leukemia

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 fewer CEBPA RNA levels and undetectable C/EBP alpha protein levels compared with other subgroups of AML patients. Conditional expression of RUNX7-CBF2T7 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.