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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 downregulation, we generated a mouse line (R26-βcat) in which high levels of active β-catenin are maintained throughout T-cell development. Young R26-βcat 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-βcat mice develop T-cell leukemias at 5 to 6 months of age. R26-βcat leukemias remain dependent on β-catenin function but lack Notch pathway activation. They exhibit recurrent secondary genomic rearrangements that lead to Myc overexpression and loss of Pten activity. Because β-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.

Original publication

DOI

10.1182/blood-2012-12-471904

Type

Journal article

Journal

Blood

Publication Date

01/08/2013

Volume

122

Pages

694 - 704

Keywords

Animals, Cell Differentiation, Gene Deletion, Gene Expression Regulation, Leukemic, Genes, myc, Mice, Mice, Transgenic, Mutation, PTEN Phosphohydrolase, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Receptors, Notch, T-Lymphocytes, Up-Regulation, Wnt Signaling Pathway, beta Catenin