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

AuthorsGonzález-García, Sara ; García-Peydró, Marina ; Martín-Gayo, Enrique ; Ballestar, Esteban; Esteller, Manel; Bornstein, Rafael; Pompa, Jose L. de la; Ferrando, Adolfo; Toribio, María Luisa
T Cell
Issue DateApr-2009
PublisherRockefeller University Press
CitationJ. Exp. Med. Vol. 206 No. 4 779-791 (2009)
AbstractNotch1 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  chain (IL-7R) expression via the CSL–MAML complex. Defective Notch1 signaling selectively impaired IL-7R 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-7R expression. The pathological implications of these findings are demonstrated by the regulation of IL-7R 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-7R.
Publisher version (URL)http://dx.doi.org/10.1084/jem.20081922
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