title: C/EBPα dysregulation in AML and ALL.
abstract: The transcription factor CCAAT/enhancer binding protein a (C/EBPα) is a critical regulator of myeloid development, directing granulocyte, and monocyte differentiation. As such, it is dysregulated in more than half of patients with acute myeloid leukemia (AML). C/EBPα expression is suppressed as result of common leukemia-associated genetic and epigenetic alterations such as AML1-ETO, BCR-ABL, FLT3-ITD, or CEBPA promoter methylation. In addition, 10-15% of patients with AML with intermediate risk cytogenetics are characterized by mutations of the CEBPA gene. Two classes of mutations are described. N-terminal changes result in expression of a truncated dominant negative C/EBPαp30 isoform. C-terminal mutations are in-frame insertions or deletions resulting in alteration of the leucine zipper preventing dimerization and DNA binding. Often, patients carry both N- and C-terminal mutations each affecting a different allele, and a mouse model recapitulates the human phenotype. Patients with mutated CEBPA AML comprise a clinically distinct group with favorable outcome consistently seen in patients with biallelic mutations. In addition, C/EBP family members are aberrantly expressing from the immunoglobulin heavy chain locus in 2% of pre-B ALLs. This review summarizes the normal hematopoietic developmental pathways regulated by C/EBPα and discusses the molecular pathways involved in mutated CEBPA AML and ALL.
authors.affiliation: Division of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Ido
authors.initials: I
authors.lastname: Paz-Priel
authors.forename: Alan
authors.initials: A
authors.lastname: Friedman
mesh_terms: D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D019175:DNA Methylation; D019281:Dimerization; D006410:Hematopoiesis / Q000502:physiology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000503:physiopathology*; D011401:Promoter Regions, Genetic
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha