β-Catenin induces T-cell transformation by promoting genomic instability (HEM4P.237)

Deregulated activation of β-catenin has been correlated with genomic instability in cancer. During thymocyte development β-catenin activates transcription in partnership with Tcf-1, an essential T-cell specific DNA-binding protein. We previously reported that targeted activation of β-catenin in thymocytes (CAT mice) induces lymphomas that depend on recombination-activating-gene (RAG) and c-Myc activities. Here we show that these lymphomas have recurring Tcra/Myc translocations that resulted from illegitimate RAG-recombination events and resembled oncogenic translocations in ponies. We therefore used the CAT animal model to obtain mechanistic insights into the transformation process. Interestingly, ChIP-seq analysis uncovered a link between Tcf-1 and RAG2 showing that the two proteins shared binding sites marked by trimethylated histone-3 lysine-4 (H3K4me3) throughout the genome, including sites near the translocation. Pre-transformed CAT thymocytes had increased DNA damage at the translocating loci and showed altered repair of RAG induced DNA double strand breaks (DSBs). Importantly these cells were able to survive despite DNA damage as activated β-catenin promoted an anti-apoptosis gene expression profile. Thus, activated β-catenin promotes genomic instability that leads to T-cell lymphomas and this is associated with compromised DSB repair and increased survival of thymocytes with damaged DNA.