title: CCAAT/enhancer binding proteins alpha and epsilon cooperate with all-trans retinoic acid in therapy but differ in their antileukemic activities.
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.
authors.affiliation: Dept of Laboratory Medicine, Box 0134, 513 Parnassus Ave, San Francisco, CA 94143, USA.
authors.forename: Young-Jin
authors.initials: YJ
authors.lastname: Lee
authors.forename: Letetia C
authors.initials: LC
authors.lastname: Jones
authors.forename: Nikolai A
authors.initials: NA
authors.lastname: Timchenko
authors.forename: Danilo
authors.initials: D
authors.lastname: Perrotti
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000502:physiology*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D006098:Granulocytes / Q000378:metabolism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D051381:Rats; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D013629:Tamoxifen / Q000494:pharmacology; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D022763:CCAAT-Enhancer-Binding Protein-alpha; D022762:CCAAT-Enhancer-Binding Proteins; C489468:Cebpe protein, mouse; C000607071:RARA protein, human; C000607072:Rara protein, mouse; C000607073:Rara protein, rat; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D013629:Tamoxifen; C070790:CEBPE protein, human; D014212:Tretinoin