Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBP alpha), in acute myeloid leukemia

The transcription factor C/EBP alpha (for CCAAT/enhancer binding protein-al pha; encoded by the gene CEBPA) is crucial for the differentiation of granu locytes. Conditional expression of C/EBP alpha triggers neutrophilic differ entiation, and no mature granulocytes are observed in Cebpa-mutant mice. He re we identify heterozygous mutations in CEBPA in ten patients with acute m yeloid leukemia (AML). We found that five mutations in the amino terminus t runcate the full-length protein, but did not affect a 30-kD protein initiat ed further downstream. The mutant proteins block wild-type C/EBP alpha DNA binding and transactivation of granulocyte target genes in a dominant-negat ive manner. and fails to induce granulocytic differentiation. Ours is the f irst report of CEBPA mutations in human neoplasia. and such mutations are l ikely to induce the differentiation block found in AML.