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CSL-MAML-dependent Notch1 signaling controls T lineage-specific IL-7R{alpha}gene expression in early human thymopoiesis and leukemia González-García, Sara García-Peydró, Marina Martín-Gayo, Enrique Ballestar Tarín, Esteban Esteller, Manel Bornstein, Rafael Pompa, José Luis de la Ferrando, Adolfo A. Toribio, María L. Expressió gènica Leucèmia Immunologia Timus (Glàndula) Gene expression Leukemia Immunology Thymus 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. 2021-05-12T13:37:37Z 2021-05-12T13:37:37Z 2009-04-13 2021-05-12T13:37:37Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Reproducció del document publicat a: https://doi.org/10.1084/jem.20081922 Journal of Experimental Medicine, 2009, vol. 206, num. 4, p. 779-791 https://doi.org/10.1084/jem.20081922 (c) Rockefeller University Press, 2009 info:eu-repo/semantics/openAccess Rockefeller University Press Articles publicats en revistes (Ciències Fisiològiques)