期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 1, 页码 391-396出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1315752111
关键词
beta-catenin/Tcf-1; DNA recombination Tcf7; Ctnnb1
资金
- National Institutes of Health [R21AI076720, R01CA158006, F31AI830542, R01GM086852]
- American Cancer Society Grant ACS/RSG [LIB-113428]
- Chicago Biomedical Consortium
- Lady Tata Memorial Trust
- Specialized Center of Research of the Leukemia and Lymphoma Society (LLS) [SCOR R7019-04]
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.
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