RARα-PLZF oncogene inhibits C/EBPα function in myeloid cells.
Proc Natl Acad Sci U S A
; 110(33): 13522-7, 2013 Aug 13.
Article
en En
| MEDLINE
| ID: mdl-23898169
ABSTRACT
In acute promyelocytic leukemia, granulocytic differentiation is arrested at the promyelocyte stage. The variant t(11;17) translocation produces two fusion proteins, promyelocytic leukemia zinc finger-retinoic acid receptor α (PLZF-RARα) and RARα-PLZF, both of which participate in leukemia development. Here we provide evidence that the activity of CCAAT/enhancer binding protein α (C/EBPα), a master regulator of granulocytic differentiation, is severely impaired in leukemic promyelocytes with the t(11;17) translocation compared with those associated with the t(15;17) translocation. We show that RARα-PLZF inhibits myeloid cell differentiation through interactions with C/EBPα tethered to DNA, using ChIP and DNA capture assays. Furthermore, RARα-PLZF recruits HDAC1 and causes histone H3 deacetylation at C/EBPα target loci, thereby decreasing the expression of C/EBPα target genes. In line with these results, HDAC inhibitors restore in part C/EBPα target gene expression. These findings provide molecular evidence for a mechanism through which RARα-PLZF acts as a modifier oncogene that subverts differentiation in the granulocytic lineage by associating with C/EBPα and inhibiting its activity.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Translocación Genética
/
Leucemia Promielocítica Aguda
/
Proteínas de Fusión Oncogénica
/
Proteína alfa Potenciadora de Unión a CCAAT
Límite:
Humans
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2013
Tipo del documento:
Article