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

Abstract

Key Points• Wnt activation, Pten loss, andMyc translocation synergize to define a novel subset of murine Notch-independent T-ALL.Wnt signaling is important for T-cell differentiation at the early CD4 2 CD8 2 stage and is subsequently downregulated with maturation. To assess the importance of this downregulation, we generated a mouse line (R26-bcat) in which high levels of active b-catenin are maintained throughout T-cell development. Young R26-bcat mice show a differentiation block at the CD4 1 CD8 1 double-positive (DP) stage. These DP cells exhibit impaired apoptosis upon irradiation or dexamethasone treatment. All R26-bcat mice develop T-cell leukemias at 5 to 6 months of age. R26-bcat leukemias remain dependent on b-catenin function but lack Notch pathway activation. They exhibit recurrent secondary genomic rearrangements that lead to Myc overexpression and loss of Pten activity. Because b-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. (Blood. 2013;122(5):694-704)

Genetic profile of T-cell acute lymphoblastic leukemias with MYC translocations

“…PTEN inactivation in primary samples as well as cell lines reflect results from experimental mouse models, which have shown that c-Myc rearrangements and Pten del exert a synergistic effect in the development of T-ALL, appearing to replace the function of Notch1. 8,16 Interestingly, PTEN del/mut and NOTCH1 mutations were mutually exclusive in our cases, confirming that they arise in different T-ALL subgroups. 17 In a unique TLX1-positive case (no.…”

Addiction to multiple oncogenes can be exploited to prevent the emergence of therapeutic resistance

“…Wnt/β-catenin pathway activation has also been observed in models of MYC-driven liver cancer, suggesting MYC and β-catenin can functionally cooperate during tumorigenesis in diverse tissue contexts (42,43). It has also been reported that lymphomas initiated by activated β-catenin frequently exhibit overexpression of MYC due to genomic amplification or rearrangement and that MYC is required for β-catenin driven lymphomagenesis (44)(45)(46), further supporting a cooperative model for MYC and β-catenin function during tumorigenesis.…”

A New View of Pathway-Driven Drug Resistance in Tumor Proliferation

“…However – irrespective of the cue and specific core pathway – cell cycle reentry and progression into the S phase will take place with the consequences unchanged, which can explain why YAP1 and β-catenin are observed in analyses of drug resistance in K-Ras4B cancers [8, 9, 20, 22, 23]. Recent studies of colorectal cancer support the independent and corresponding roles of PI3K and β-catenin in the cell cycle G1 phase.…”