CCAAT/enhancer binding proteins alpha and epsilon cooperate with all-trans retinoic acid in therapy but differ in their antileukemic activities

Blood. 2006 Oct 1;108(7):2416-9. doi: 10.1182/blood-2006-02-003582. Epub 2006 Jun 20.

Abstract

CCAAT/enhancer binding proteins (C/EBPs) play critical roles in myelopoiesis. Dysregulation of these proteins likely contributes to the pathogenesis of myeloid disorders characterized by a block in granulopoiesis. In one such disease, acute promyelocytic leukemia (APL), a promyelocytic leukemia-retinoic acid receptor alpha (PML-RARalpha) fusion protein is expressed as a result of a t(15;17) chromosomal translocation. Treatment of PML-RARalpha leukemic cells with all-trans retinoic acid (ATRA) causes them to differentiate into mature neutrophils, an effect thought to be mediated by C/EBPs. In this study, we assess the potential for cooperativity between increased C/EBP activity and ATRA therapy. We demonstrate that although both C/EBPalpha and C/EBPepsilon can significantly prolong survival in a mouse model of APL, they are not functionally equivalent in this capacity. We also show that forced expression of C/EBPalpha or C/EBPepsilon in combination with ATRA treatment has a synergistic effect on survival of leukemic mice compared with either therapy alone.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Hormonal / pharmacology
  • CCAAT-Enhancer-Binding Protein-alpha / physiology*
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • CCAAT-Enhancer-Binding Proteins / physiology*
  • Granulocytes / metabolism
  • Humans
  • Leukemia, Promyelocytic, Acute / drug therapy*
  • Leukemia, Promyelocytic, Acute / metabolism
  • Mice
  • Rats
  • Receptors, Retinoic Acid / metabolism
  • Retinoic Acid Receptor alpha
  • Tamoxifen / pharmacology
  • Tretinoin / metabolism*

Substances

  • Antineoplastic Agents, Hormonal
  • CCAAT-Enhancer-Binding Protein-alpha
  • CCAAT-Enhancer-Binding Proteins
  • Cebpe protein, mouse
  • RARA protein, human
  • Rara protein, mouse
  • Rara protein, rat
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Tamoxifen
  • CEBPE protein, human
  • Tretinoin