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

D Kaveri, P Kastner, D Dembélé… - Blood, The Journal …, 2013 - ashpublications.org
D Kaveri, P Kastner, D Dembélé, C Nerlov, S Chan, P Kirstetter
Blood, The Journal of the American Society of Hematology, 2013ashpublications.org
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 …
Abstract
Wnt signaling is important for T-cell differentiation at the early CD4CD8 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.
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