title: Hes1 is a critical but context-dependent mediator of canonical Notch signaling in lymphocyte development and transformation.
abstract: Although canonical Notch signaling regulates multiple hematopoietic lineage decisions including T cell and marginal zone B cell fate specification, the downstream molecular mediators of Notch function are largely unknown. We showed here that conditional inactivation of Hes1, a well-characterized Notch target gene, in adult murine bone marrow (BM) cells severely impaired T cell development without affecting other Notch-dependent hematopoietic lineages such as marginal zone B cells. Competitive mixed BM chimeras, intrathymic transfer experiments, and in vitro culture of BM progenitors on Delta-like-expressing stromal cells further demonstrated that Hes1 is required for T cell lineage commitment, but dispensable for Notch-dependent thymocyte maturation through and beyond the beta selection checkpoint. Furthermore, our data strongly suggest that Hes1 is essential for the development and maintenance of Notch-induced T cell acute lymphoblastic leukemia. Collectively, our studies identify Hes1 as a critical but context-dependent mediator of canonical Notch signaling in the hematopoietic system.
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne (EPFL), Swiss Institute for Experimental Cancer Research (ISREC), Station 19, 1015 Lausanne, Switzerland.
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Wendorff
authors.forename: Ute
authors.initials: U
authors.lastname: Koch
authors.forename: F Thomas
authors.initials: FT
authors.lastname: Wunderlich
authors.forename: Silvia
authors.initials: S
authors.lastname: Wirth
authors.forename: Christelle
authors.initials: C
authors.lastname: Dubey
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
authors.forename: H Robson
authors.initials: HR
authors.lastname: MacDonald
authors.forename: Freddy
authors.initials: F
authors.lastname: Radtke
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics*; D008213:Lymphocyte Activation / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000276:immunology; D051880:Receptors, Notch / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse