CSL-MAML-dependent Notch1 signaling controls T lineage-specific IL-7R{alpha}gene expression in early human thymopoiesis and leukemia

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...

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Detalles Bibliográficos
Autores: González-García, Sara, García-Peydró, Marina, Martín-Gayo, Enrique, Ballestar Tarín, Esteban, Esteller, Manel, 1968-, Bornstein, Rafael, Pompa, José Luis de la, Ferrando, Adolfo A., Toribio, María L.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2009
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/177169
Acceso en línea:https://hdl.handle.net/2445/177169
Access Level:acceso abierto
Palabra clave:Expressió gènica
Leucèmia
Immunologia
Timus (Glàndula)
Gene expression
Leukemia
Immunology
Thymus
Descripción
Sumario: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.

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