CSL-MAML-dependent Notch1 signaling controls T lineage-specific IL-7R{alpha} gene expression in early human thymopoiesis and leukemia.
J Exp Med
; 206(4): 779-91, 2009 Apr 13.
Article
em En
| MEDLINE
| ID: mdl-19349467
ABSTRACT
Notch1 activation is essential for T-lineage specification of lymphomyeloid progenitors seeding the thymus. Progression along the T cell lineage further requires cooperative signaling provided by the interleukin 7 receptor (IL-7R), but the molecular mechanisms responsible for the dynamic and lineage-specific regulation of IL-7R during thymopoiesis are unknown. We show that active Notch1 binds to a conserved CSL-binding site in the human IL7R gene promoter and critically regulates IL7R transcription and IL-7R alpha chain (IL-7Ralpha) expression via the CSL-MAML complex. Defective Notch1 signaling selectively impaired IL-7Ralpha expression in T-lineage cells, but not B-lineage cells, and resulted in a compromised expansion of early human developing thymocytes, which was rescued upon ectopic IL-7Ralpha expression. The pathological implications of these findings are demonstrated by the regulation of IL-7Ralpha expression downstream of Notch1 in T cell leukemias. Thus, Notch1 controls early T cell development, in part by regulating the stage- and lineage-specific expression of IL-7Ralpha.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Timo
/
Linfócitos T
/
Leucemia
/
Regulação da Expressão Gênica
/
Receptores de Interleucina-7
Limite:
Animals
/
Humans
/
Newborn
Idioma:
En
Revista:
J Exp Med
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Espanha