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Stabilization of b-catenin induces lymphomas

ABSTRACT: Activation of b-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 preTCR signaling. We show here that activated b-catenin stalls the developmental transition from the double-positive (DP) to the single-positive (SP) thymocyte stage and predisposes DP thymocytes to transformation. b-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 upregulation of c-Myc, whose activity is required for transformation since its conditional ablation abrogates lymphomagenesis. In contrast, the expression of Notch receptors as well as targets is reduced in DP thymocytes with stabilized b-catenin and remains low in the lymphomas indicating that Notch activation is not required or selected for in b-catenin induced lymphomas. Thus, b-catenin activation may provide a mechanism for the induction of T-ALL that does not depend on Notch activation. Keywords: Lckcre, CD4Cre-Ctnnbex3, lymphoma, gene expression

ORGANISM(S): Mus musculus

PROVIDER: GSE7050 | GEO | 2007/02/17

SECONDARY ACCESSION(S): PRJNA98513

REPOSITORIES: GEO

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Transcription profiling of mouse LckCre, CD4Cre-Ctnnbex3 mutants before and after T-cell transformation reveals stabilization of b-catenin induces lymphomas

Project description:Activation of b-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 preTCR signaling. We show here that activated b-catenin stalls the developmental transition from the double-positive (DP) to the single-positive (SP) thymocyte stage and predisposes DP thymocytes to transformation. b-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 upregulation of c-Myc, whose activity is required for transformation since its conditional ablation abrogates lymphomagenesis. In contrast, the expression of Notch receptors as well as targets is reduced in DP thymocytes with stabilized b-catenin and remains low in the lymphomas indicating that Notch activation is not required or selected for in b-catenin induced lymphomas. Thus, b-catenin activation may provide a mechanism for the induction of T-ALL that does not depend on Notch activation. Experiment Overall Design: This study was used to compare gene expression patterns of LckCre mice, CD4Cre-Ctnnbex3 mice before and after T-cell transformation. 5 independent Lckcre (control), 5 independent CD4Cre-Ctnnbex3 mice and 8 independent mice with lymphomas were used. Thymocytes or tumor masses were collected from Lckcre, CD4Cre-Ctnnbex3 mice. Total RNA isolation and purification followed by synthesis of dscDNA, Biotinylated cRNA and purification of Biotinylated cRNA. Then the hybridization to Affymetrix âMouse Expression Array 430 Genechipsâ was done. Data was analysed by dchip.

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