title: CCAAT/Enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia.
abstract: CCAAT/enhancer binding proteins (C/EBPs) are a family of factors that regulate cell growth and differentiation. These factors, particularly C/EBPalpha and C/EBPepsilon, have important roles in normal myelopoiesis. In addition, loss of C/EBP activity appears to have a role in the pathogenesis of myeloid disorders including acute myeloid leukemia (AML). Acute promyelocytic leukemia (APL) is a subtype of AML in which a role for C/EBPs has been postulated. In almost all cases of APL, a promyelocytic leukemia-retinoic acid receptor alpha (PML-RARalpha) fusion protein is expressed as a result of a t(15;17)(q22;q12) chromosomal translocation. PML-RARalpha inhibits expression of C/EBPepsilon, whereas all-trans retinoic acid (tRA), a differentiating agent to which APL is particularly susceptible, induces C/EBPepsilon expression. PML-RARalpha may also inhibit C/EBPalpha activity. Thus, the effects of PML-RARalpha on C/EBPs may contribute to both the development of leukemia and the unique sensitivity of APL to tRA. We tested the hypothesis that increasing the activity of C/EBPs would revert the leukemic phenotype. C/EBPalpha and C/EBPepsilon were introduced into the FDC-P1 myeloid cell line and into leukemic cells from PML-RARA transgenic mice. C/EBP factors suppressed growth and induced partial differentiation in vitro. In vivo, enhanced expression of C/EBPs prolonged survival. By using a tamoxifen-responsive version of C/EBPepsilon, we observed that C/EBPepsilon could mimic the effect of tRA, driving neutrophilic differentiation in leukemic animals. Our results support the hypothesis that induction of C/EBP activity is a critical effect of tRA in APL. Furthermore, our findings suggest that targeted modulation of C/EBP activities could provide a new approach to therapy of AML.
authors.affiliation: Comprehensive Cancer Center and Department of Laboratory Medicine, University of California, San Francisco 94143-0128, USA.
authors.forename: Bao-Tran H
authors.initials: BT
authors.lastname: Truong
authors.forename: Young-Jin
authors.initials: YJ
authors.lastname: Lee
authors.forename: Tracey A
authors.initials: TA
authors.lastname: Lodie
authors.forename: Dorothy J
authors.initials: DJ
authors.lastname: Park
authors.forename: Danilo
authors.initials: D
authors.lastname: Perrotti
authors.forename: Naohide
authors.initials: N
authors.lastname: Watanabe
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakajima
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
mesh_terms: D000208:Acute Disease; D000818:Animals; D000970:Antineoplastic Agents; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000502:physiology; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D002455:Cell Division; D006801:Humans; D007951:Leukemia, Myeloid / Q000209:etiology*; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D014161:Transduction, Genetic; D014212:Tretinoin; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D022763:CCAAT-Enhancer-Binding Protein-alpha; D022762:CCAAT-Enhancer-Binding Proteins; C489468:Cebpe protein, mouse; C070790:CEBPE protein, human; D014212:Tretinoin