Alternative promoter usage at the Notch1 locus supports ligand-independent signaling in T cell development and leukemogenesis.
Immunity
; 33(5): 685-98, 2010 Nov 24.
Article
en En
| MEDLINE
| ID: mdl-21093322
ABSTRACT
Loss of the transcription factor Ikaros is correlated with Notch receptor activation in T cell acute lymphoblastic leukemia (T-ALL). However, the mechanism remains unknown. We identified promoters in Notch1 that drove the expression of Notch1 proteins in the absence of a ligand. Ikaros bound to both canonical and alternative Notch1 promoters and its loss increased permissive chromatin, facilitating recruitment of transcription regulators. At early stages of leukemogenesis, increased basal expression from the canonical and 5'-alternative promoters initiated a feedback loop, augmenting Notch1 signaling. Ikaros also repressed intragenic promoters for ligand-independent Notch1 proteins that are cryptic in wild-type cells, poised in preleukemic cells, and active in leukemic cells. Only ligand-independent Notch1 isoforms were required for Ikaros-mediated leukemogenesis. Notch1 alternative-promoter usage was observed during T cell development and T-ALL progression. Thus, a network of epigenetic and transcriptional regulators controls conventional and unconventional Notch signaling during normal development and leukemogenesis.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Activación de Linfocitos
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Transducción de Señal
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Regulación Leucémica de la Expresión Génica
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Regiones Promotoras Genéticas
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Receptor Notch1
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Leucemia-Linfoma Linfoblástico de Células T Precursoras
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Immunity
Asunto de la revista:
ALERGIA E IMUNOLOGIA
Año:
2010
Tipo del documento:
Article
País de afiliación:
España