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

¹ Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid, Madrid 28049, Spain
² Centro Nacional de Investigaciones Oncológicas, Madrid 28029, Spain
³ Madrid Cord Blood Bank and Department of Hematology, Hospital Universitario 12 de Octubre, Madrid 28041, Spain
⁴ Centro Nacional de Biotecnología, CSIC, Madrid 28049, Spain
⁵ Institute for Cancer Genetics, Columbia University, New York, NY 10032

CORRESPONDENCE María L. Toribio: mtoribio{at}cbm.uam.es

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 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.

Abbreviations used: c, common cytokine receptor ; CB, cord blood; ChIP; chromatin immunoprecipitation; CompE, compound E; DN, double negative; dnMAML1, dominant-negative MAML1; DP, double positive; ETP, early thymic progenitor; FTOC, fetal thymic organ culture; GABP, GA binding protein; GSI, -secretase inhibitor; ICN1, intracellular Notch1; MEF, mouse embryonic fibroblast; MFI, mean fluorescence intensity; mRNA, messenger RNA; T-ALL, T cell acute lymphoblastic leukemia.

© 2009 González-García et al.
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