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

Blood. 2013 Aug 1;122(5):694-704. doi: 10.1182/blood-2012-12-471904. Epub 2013 Jun 25.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Gene Deletion
  • Gene Expression Regulation, Leukemic
  • Genes, myc / genetics*
  • Mice
  • Mice, Transgenic
  • Mutation / physiology
  • PTEN Phosphohydrolase / genetics*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / mortality
  • Receptors, Notch / genetics
  • Receptors, Notch / physiology*
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / physiology
  • Up-Regulation / genetics
  • Wnt Signaling Pathway / genetics
  • Wnt Signaling Pathway / physiology
  • beta Catenin / agonists
  • beta Catenin / genetics
  • beta Catenin / metabolism
  • beta Catenin / physiology*

Substances

  • Receptors, Notch
  • beta Catenin
  • PTEN Phosphohydrolase
  • Pten protein, mouse