期刊
BLOOD
卷 122, 期 5, 页码 694-704出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-12-471904
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资金
- Fondation ARC
- Fondation de France
- La Ligue Contre le Cancer (equipe labellisee)
- Institut National du Cancer
- Institut National de la Sante et de la Recherche Medicale
- Centre National de la Recherche Scientifique
- Universite de Strasbourg
- Institut de Genetique et de Biologie Moleculaire et Cellulaire International PhD program
- Fondation pour la Recherche Medicale
- MRC [G0701761] Funding Source: UKRI
- Medical Research Council [G0701761] Funding Source: researchfish
Wnt signaling is important for T-cell differentiation at the early CD4(-)CD8(-) stage and is subsequently downregulated with maturation. To assess the importance of this down-regulation, we generated a mouse line (R26-beta cat) in which high levels of active beta-catenin are maintained throughout T-cell development. Young R26-beta cat mice show a differentiation block at the CD4(+)CD8(+) double-positive (DP) stage. These DP cells exhibit impaired apoptosis upon irradiation or dexamethasone treatment. All R26-beta cat mice develop T-cell leukemias at 5 to 6 months of age. R26-beta cat leukemias remain dependent on beta-catenin function but lack Notch pathway activation. They exhibit recurrent secondary genomic rearrangements that lead to Myc overexpression and loss of Pten activity. Because beta-catenin activation and Myc translocations were previously found in murine T-cell acute lymphoblastic leukemias (T-ALLs) deficient for Pten, our results suggest that activation of the canonical Wnt pathway is associated with a subtype of Notch-independent T-ALLs that bear Myc gene rearrangements and Pten mutations.
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