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

S González-García, M García-Peydró… - Journal of Experimental …, 2009 - rupress.org
S González-García, M García-Peydró, E Martín-Gayo, E Ballestar, M Esteller, R Bornstein…
Journal of Experimental Medicine, 2009rupress.org
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 α chain (IL …
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 α chain (IL-7Rα) expression via the CSL–MAML complex. Defective Notch1 signaling selectively impaired IL-7Rα 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-7Rα expression. The pathological implications of these findings are demonstrated by the regulation of IL-7Rα 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-7Rα.
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