title: Beta-catenin stabilization stalls the transition from double-positive to single-positive stage and predisposes thymocytes to malignant transformation.
abstract: Activation of beta-catenin has been causatively linked to the etiology of colon cancer. Conditional stabilization of this molecule in pro-T cells promotes thymocyte development without the requirement for pre-TCR signaling. We show here that activated beta-catenin stalls the developmental transition from the double-positive (DP) to the single-positive (SP) thymocyte stage and predisposes DP thymocytes to transformation. beta-Catenin-induced thymic lymphomas have a leukemic arrest at the early DP stage. Lymphomagenesis requires Rag activity, which peaks at this developmental stage, as well as additional secondary genetic events. A consistent secondary event is the transcriptional up-regulation of c-Myc, whose activity is required for transformation because its conditional ablation abrogates lymphomagenesis. In contrast, the expression of Notch receptors as well as targets is reduced in DP thymocytes with stabilized beta-catenin and remains low in the lymphomas, indicating that Notch activation is not required or selected for in beta-catenin-induced lymphomas. Thus, beta-catenin activation may provide a mechanism for the induction of T-cell-acute lymphoblastic leukemia (T-ALL) that does not depend on Notch activation.
authors.affiliation: Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, MA 02111, USA.
authors.forename: Zhuyan
authors.initials: Z
authors.lastname: Guo
authors.forename: Marei
authors.initials: M
authors.lastname: Dose
authors.forename: Damian
authors.initials: D
authors.lastname: Kovalovsky
authors.forename: Rui
authors.initials: R
authors.lastname: Chang
authors.forename: Jennifer
authors.initials: J
authors.lastname: O'Neil
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
authors.forename: Harald
authors.initials: H
authors.lastname: von Boehmer
authors.forename: Khashayarsha
authors.initials: K
authors.lastname: Khazaie
authors.forename: Fotini
authors.initials: F
authors.lastname: Gounari
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D018398:Homeodomain Proteins; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000209:etiology; D016399:Lymphoma, T-Cell / Q000209:etiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016271:Proto-Oncogene Proteins c-myc; D051880:Receptors, Notch; D013601:T-Lymphocytes / Q000473:pathology; D013950:Thymus Gland / Q000166:cytology*; D051176:beta Catenin / Q000502:physiology*
chemical_list: D018398:Homeodomain Proteins; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D051880:Receptors, Notch; D051176:beta Catenin; C064658:RAG-1 protein