CCAAT/enhancer binding protein epsilon is a potential retinoid target gene in acute promyelocytic leukemia treatment

J Clin Invest. 1999 May 15;103(10):1399-408. doi: 10.1172/JCI2887.


The CCAAT/enhancer binding protein epsilon (C/EBPepsilon) is a nuclear transcription factor expressed predominantly in myeloid cells and implicated as a potential regulator of myeloid differentiation. We show that it was rapidly induced in the acute promyelocytic leukemia (APL) cell line NB4 during granulocytic differentiation after exposure to retinoic acid (RA). Our data suggest that induction of C/EBPepsilon expression was through the retinoic acid receptor alpha (RARalpha) pathway. Reporter gene studies showed that C/EBPepsilon promoter/enhancer activity increased in a retinoid-dependent fashion via the retinoic acid response element (RARE) present in the promoter region of C/EBPepsilon. The RA-induced expression of C/EBPepsilon markedly increased in U937 myelomonoblasts that were induced to express promyelocytic leukemia/RARalpha (PML/RARalpha), but not in those induced to express promyelocytic leukemia zinc finger/RARalpha (PLZF/RARalpha). In retinoid-resistant APL cell lines, C/EBPepsilon either is not induced or is induced only at very high concentrations of RA (>/=10(-6) M). In addition, forced expression of C/EBPepsilon in the U937 myelomonoblastic leukemia cells mimicked terminal granulocytic differentiation, including morphologic changes, increased CD11b/CD66b expression, and induction of secondary granule protein expression. Our data strongly suggest that C/EBPepsilon is a downstream target gene responsible for RA-induced granulocytic differentiation of APL cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • CCAAT-Enhancer-Binding Proteins
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • DNA-Binding Proteins / genetics*
  • Drug Resistance / genetics
  • Enhancer Elements, Genetic
  • Gene Expression / drug effects
  • Genes, Reporter
  • Humans
  • Leukemia, Promyelocytic, Acute / drug therapy*
  • Leukemia, Promyelocytic, Acute / genetics*
  • Leukemia, Promyelocytic, Acute / metabolism
  • Nuclear Proteins / genetics*
  • Promoter Regions, Genetic
  • Receptors, Retinoic Acid / metabolism
  • Retinoic Acid Receptor alpha
  • Retinoids / therapeutic use*
  • Tretinoin / pharmacology
  • Tumor Cells, Cultured
  • U937 Cells


  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins
  • Nuclear Proteins
  • RARA protein, human
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Retinoids
  • Tretinoin