β-Catenin induces T-cell transformation by promoting genomic instability

Marei Dose, Akinola Olumide Emmanuel, Julie Chaumeil, Jiangwen Zhang, Tianjiao Sun, Kristine Germar, Katayoun Aghajani, Elizabeth M. Davis, Shilpa Keerthivasan, Andrea L. Bredemeyer, Barry P. Sleckman, Steven T. Rosen, Jane A. Skok, Michelle M. Le Beau, Katia Georgopoulos, Fotini Gounari

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Deregulated activation of β-catenin in cancer has been correlated with genomic instability. During thymocyte development, β-catenin activates transcription in partnership with T-cell-specific transcription factor 1 (Tcf-1). We previously reported that targeted activation of β-catenin in thymocytes (CAT mice) induces lymphomas that depend on recombination activating gene (RAG) and myelocytomatosis oncogene (Myc) activities. Here we show that these lymphomas have recurring Tcra/Myc translocations that resulted from illegitimate RAG recombination events and resembled oncogenic translocations previously described in human TALL. We therefore used the CAT animal model to obtain mechanistic insights into the transformation process. 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 near the translocation sites. Pretransformed CAT thymocytes had increased DNA damage at the translocating loci and showed altered repair of RAG-induced DNA double strand breaks. These cells were able to survive despite DNA damage because activated β-catenin promoted an antiapoptosis gene expression profile. Thus, activated β-catenin promotes genomic instability that leads to T-cell lymphomas as a consequence of altered double strand break repair and increased survival of thymocytes with damaged DNA.

Original languageEnglish
Pages (from-to)391-396
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number1
DOIs
StatePublished - 2014

Keywords

  • Beta-catenin/Tcf-1
  • Ctnnb1
  • DNA recombination Tcf7

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