Expression of p15(ink4b) gene during megakaryocytic differentiation of normal and myelodysplastic hematopoietic progenitors.
Blood
; 98(2): 495-7, 2001 Jul 15.
Article
en En
| MEDLINE
| ID: mdl-11435325
ABSTRACT
In myelodysplastic syndrome (MDS), the expression of the cyclin-dependent kinase inhibitor p15(ink4B) (p15) is frequently decreased because of the aberrant methylation of the gene promoter; p15 is normally up-regulated during megakaryocytic differentiation. It was hypothesized that p15 methylation and deregulation of gene expression contribute to defective megakaryocytopoiesis in patients with MDS. Here it is shown that the increasing autocrine production of TGF-beta1 stimulates megakaryocytic differentiation in normal CD34(+) cells and that p15 mediates, at least in part, this effect. This TGF-beta1-dependent pathway is altered in MDS CD34(+) progenitors because of p15 methylation. The demethylating agent 2-deoxyAZAcytidin can restore the normal demethylated state of the p15 gene and increase its expression. Nevertheless, MDS CD34(+) cells only poorly differentiate to the megakaryocytic lineage. These findings suggest that p15 methylation occurs in a neoplastic clone with a profound defect of cell proliferation, survival, and differentiation that cannot be overcome by using a demethylating drug.
Buscar en Google
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Síndromes Mielodisplásicos
/
Células Madre Hematopoyéticas
/
Megacariocitos
/
Proteínas Portadoras
/
Expresión Génica
/
Diferenciación Celular
/
Proteínas de Ciclo Celular
/
Inhibidor p16 de la Quinasa Dependiente de Ciclina
/
Proteínas Supresoras de Tumor
Límite:
Humans
Idioma:
En
Revista:
Blood
Año:
2001
Tipo del documento:
Article
País de afiliación:
Italia