| First Author | Dose M | Year | 2014 |
| Journal | Proc Natl Acad Sci U S A | Volume | 111 |
| Issue | 1 | Pages | 391-6 |
| PubMed ID | 24371308 | Mgi Jnum | J:206374 |
| Mgi Id | MGI:5550165 | Doi | 10.1073/pnas.1315752111 |
| Citation | Dose M, et al. (2014) beta-Catenin induces T-cell transformation by promoting genomic instability. Proc Natl Acad Sci U S A 111(1):391-6 |
| abstractText | Deregulated activation of beta-catenin in cancer has been correlated with genomic instability. During thymocyte development, beta-catenin activates transcription in partnership with T-cell-specific transcription factor 1 (Tcf-1). We previously reported that targeted activation of beta-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 T-ALL. 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 beta-catenin promoted an antiapoptosis gene expression profile. Thus, activated beta-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. |
