title: Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias.
abstract: The CCAAT/enhancer binding protein alpha (C/EBPalpha) protein is essential for proper lung and liver function and granulocytic and adipose tissue differentation. It was hypothesized that abnormalties in C/EBPalpha function contribute to the development of malignancies in a variety of tissues. To test this, genomic DNA from 408 patient samples and 5 cell lines representing 11 different cancers was screened for mutations in the C/EBPalpha gene. Two silent polymorphisms termed P1 and P2 were present at frequencies of 13.5% and 2.2%, respectively. Of the 12 mutations detected in 10 patients, silent changes were identified in one nonsmall cell lung cancer, one prostate cancer, and one acute myelogenous leukemia (AML) subtype M4. The 9 remaining mutations were detected in 1 of 92 (1.1%) myelodysplastic syndrome (MDS) samples and 6 of 78 (7.7%) AML (AML-M2 and AML-M4) samples. Some mutations truncated the predicted protein with loss of the DNA-binding (basic region) and dimerization (leucine zipper [ZIP]) domains by either deletions or nonsense codons. Also, inframe deletions or insertions in the fork region located between the leucine zipper and basic region, or within the leucine zipper, disrupted the alpha-helical phase of the bZIP domain. The inframe deletion and insertion mutations abrogated the transcriptional activation function of C/EBPalpha on the granulocyte colony-stimulating factor receptor promoter. These mutants localized properly to the nucleus, but were unable to bind to the C/EBP site in the promoter and did not possess dominant-negative activity. The mutations in the MDS patient and one AML-M2 patient were biallelic, indicating a loss of C/EBPalpha function. These results suggest that mutation of C/EBPalpha is involved in specific subtypes of AML and in MDS, but may occur rarely in other types of leukemias or nonhematologic malignancies.
authors.affiliation: Cedars-Sinai Medical Center, Burns and Allen Research Institute, Division of Hematology/Oncology, University of California-Los Angeles School of Medicine, 90048, USA. gombarta@csmc.edu
authors.forename: Adrian F
authors.initials: AF
authors.lastname: Gombart
authors.forename: Wolf-K
authors.initials: WK
authors.lastname: Hofmann
authors.forename: Seiji
authors.initials: S
authors.lastname: Kawano
authors.forename: Seisho
authors.initials: S
authors.lastname: Takeuchi
authors.forename: Utz
authors.initials: U
authors.lastname: Krug
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kwok
authors.forename: Renee J
authors.initials: RJ
authors.lastname: Larsen
authors.forename: Hiroya
authors.initials: H
authors.lastname: Asou
authors.forename: Carl W
authors.initials: CW
authors.lastname: Miller
authors.forename: Dieter
authors.initials: D
authors.lastname: Hoelzer
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D000208:Acute Disease; D000595:Amino Acid Sequence; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics* / Q000494:pharmacology / Q000502:physiology; D004252:DNA Mutational Analysis; D016147:Genes, Tumor Suppressor / Q000502:physiology; D005820:Genetic Testing; D006801:Humans; D007951:Leukemia, Myeloid / Q000209:etiology / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000209:etiology / Q000235:genetics*; D011110:Polymorphism, Genetic; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D014157:Transcription Factors