β-Catenin activation synergizes with Pten loss and Myc overexpression in Notch-independent T-ALL

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.