Beta-catenin stabilization stalls the transition from double-positive to single-positive stage and predisposes thymocytes to malignant transformation
Authors
Guo, ZhuyanDose, Marei
Kovalovsky, Damian
Chang, Rui
O'Neil, Jennifer Elinor
Look, A. Thomas
von Boehmer, Harald
Khazaie, Khashayarsha
Gounari, Fotini
UMass Chan Affiliations
Department of Molecular Genetics and MicrobiologyGraduate School of Biomedical Sciences
Document Type
Journal ArticlePublication Date
2007-02-24Keywords
Animals; Cell Transformation, Neoplastic; Homeodomain Proteins; Leukemia-Lymphoma, Adult T-Cell; Lymphoma, T-Cell; Mice; Mice, Knockout; Proto-Oncogene Proteins c-myc; Receptors, Notch; T-Lymphocytes; Thymus Gland; beta CateninLife Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
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.Source
Blood. 2007 Jun 15;109(12):5463-72. Epub 2007 Feb 22. Link to article on publisher's siteDOI
10.1182/blood-2006-11-059071Permanent Link to this Item
http://hdl.handle.net/20.500.14038/32840PubMed ID
17317856Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1182/blood-2006-11-059071