title: Alternative promoter usage at the Notch1 locus supports ligand-independent signaling in T cell development and leukemogenesis.
abstract: Loss of the transcription factor Ikaros is correlated with Notch receptor activation in T cell acute lymphoblastic leukemia (T-ALL). However, the mechanism remains unknown. We identified promoters in Notch1 that drove the expression of Notch1 proteins in the absence of a ligand. Ikaros bound to both canonical and alternative Notch1 promoters and its loss increased permissive chromatin, facilitating recruitment of transcription regulators. At early stages of leukemogenesis, increased basal expression from the canonical and 5'-alternative promoters initiated a feedback loop, augmenting Notch1 signaling. Ikaros also repressed intragenic promoters for ligand-independent Notch1 proteins that are cryptic in wild-type cells, poised in preleukemic cells, and active in leukemic cells. Only ligand-independent Notch1 isoforms were required for Ikaros-mediated leukemogenesis. Notch1 alternative-promoter usage was observed during T cell development and T-ALL progression. Thus, a network of epigenetic and transcriptional regulators controls conventional and unconventional Notch signaling during normal development and leukemogenesis.
authors.affiliation: Vascular Biology and Inflammation Department, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Gómez-del Arco
authors.forename: Mariko
authors.initials: M
authors.lastname: Kashiwagi
authors.forename: Audrey F
authors.initials: AF
authors.lastname: Jackson
authors.forename: Taku
authors.initials: T
authors.lastname: Naito
authors.forename: Jiangwen
authors.initials: J
authors.lastname: Zhang
authors.forename: Feifei
authors.initials: F
authors.lastname: Liu
authors.forename: Barbara
authors.initials: B
authors.lastname: Kee
authors.forename: Marc
authors.initials: M
authors.lastname: Vooijs
authors.forename: Freddy
authors.initials: F
authors.lastname: Radtke
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Redondo
authors.forename: Katia
authors.initials: K
authors.lastname: Georgopoulos
mesh_terms: D000818:Animals; D057890:Epigenomics; D015973:Gene Expression Regulation, Leukemic; D056426:Genetic Loci; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics*; D051379:Mice; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor