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-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.
González-García
Sara
S
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain.
García-Peydró
Marina
M
Martín-Gayo
Enrique
E
Ballestar
Esteban
E
Esteller
Manel
M
Bornstein
Rafael
R
de la Pompa
José Luis
JL
Ferrando
Adolfo A
AA
Toribio
María L
ML
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D005312:Fetal Blood / Q000276:immunology; D005333:Fetus / Q000276:immunology; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007231:Infant, Newborn; D007938:Leukemia / Q000235:genetics / Q000276:immunology*; D051379:Mice; D009924:Organ Culture Techniques; D051881:Receptor, Notch1 / Q000276:immunology; D020395:Receptors, Interleukin-7 / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000254:growth & development / Q000276:immunology*
D015703:Antigens, CD; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain