Biallelic mutations in the CEBPA gene and low CEBPA expression levels as prognostic markers in intermediate-risk AML

Hematol J. 2003;4(1):31-40. doi: 10.1038/sj.thj.6200216.


The CCAAT/enhancer binding protein alpha is an essential transcription factor for granulocytic differentiation. Recent studies reported N- and C-terminal CEBPA mutations in approximately 7% of acute myeloid leukaemia (AML) patients. C-terminal mutations are usually in-frame and occur in the basic-leucine zipper (bZIP) domain, resulting in deficient DNA binding. Using a rapid PCR approach, we screened for bZIP mutations and determined the prognostic value of these mutations in a cohort of 277 de novo AMLs. In addition, we set out to quantify CEBPA mRNA levels by 'real-time' PCR using TaqMan technology. In-frame insertions were observed in 12 (4.3%) cases. All cases with mutations carried an intermediate-risk karyotype and all but one belonged to M1 or M2 FAB class. Further sequence analysis revealed that CEBPA C-terminal mutations are associated with frameshift mutations in the N-terminus of CEBPA. These two mutations were always found in different alleles. Event-free survival (EFS) and overall survival (OS) of patients with CEBPA mutations were significantly increased (P=0.02 and 0.03, respectively) in comparison to the patients lacking these mutations. Mutations were associated with a significantly reduced hazard ratio for death (OS: HR=0.35, P=0.04) and failure (EFS: no CR, death in CR or relapse, HR=0.37, P=0.03). This favourable hazard ratio was maintained after adjustment for cytogenetic risk, FLT3-ITD and CEBPA expression levels in multivariable analysis. In contrast, low CEBPA expression in AML with intermediate-risk karyotype (n=6) seemed to be associated with poor prognosis (not significant). By including this newly developed PCR assay, we define a subgroup of good-risk patients within the heterogeneous intermediate-risk group of AML.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adolescent
  • Adult
  • Alleles
  • Amino Acid Sequence
  • Binding Sites
  • CCAAT-Enhancer-Binding Protein-alpha / biosynthesis
  • CCAAT-Enhancer-Binding Protein-alpha / deficiency
  • CCAAT-Enhancer-Binding Protein-alpha / genetics*
  • DNA Mutational Analysis
  • DNA, Complementary / genetics
  • DNA, Neoplasm / genetics
  • Disease-Free Survival
  • Female
  • Frameshift Mutation
  • Gene Expression Regulation, Leukemic*
  • Humans
  • Karyotyping
  • Leucine Zippers / genetics
  • Leukemia, Myeloid / genetics*
  • Leukemia, Myeloid / metabolism
  • Leukemia, Myeloid / mortality
  • Life Tables
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutagenesis, Insertional
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / deficiency
  • Neoplasm Proteins / genetics*
  • Neoplastic Stem Cells / metabolism
  • Prognosis
  • Protein Structure, Tertiary
  • RNA, Messenger / biosynthesis
  • RNA, Neoplasm / biosynthesis
  • Remission Induction
  • Risk
  • Risk Factors
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Survival Analysis


  • CCAAT-Enhancer-Binding Protein-alpha
  • DNA, Complementary
  • DNA, Neoplasm
  • Neoplasm Proteins
  • RNA, Messenger
  • RNA, Neoplasm