title: β-Catenin induces T-cell transformation by promoting genomic instability.
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 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 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.
authors.affiliation: Section of Rheumatology and Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL 60637.
authors.forename: Marei
authors.initials: M
authors.lastname: Dose
authors.forename: Akinola Olumide
authors.initials: AO
authors.lastname: Emmanuel
authors.forename: Julie
authors.initials: J
authors.lastname: Chaumeil
authors.forename: Jiangwen
authors.initials: J
authors.lastname: Zhang
authors.forename: Tianjiao
authors.initials: T
authors.lastname: Sun
authors.forename: Kristine
authors.initials: K
authors.lastname: Germar
authors.forename: Katayoun
authors.initials: K
authors.lastname: Aghajani
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Davis
authors.forename: Shilpa
authors.initials: S
authors.lastname: Keerthivasan
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Bredemeyer
authors.forename: Barry P
authors.initials: BP
authors.lastname: Sleckman
authors.forename: Steven T
authors.initials: ST
authors.lastname: Rosen
authors.forename: Jane A
authors.initials: JA
authors.lastname: Skok
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
authors.forename: Katia
authors.initials: K
authors.lastname: Georgopoulos
authors.forename: Fotini
authors.initials: F
authors.lastname: Gounari
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002470:Cell Survival; D053903:DNA Breaks, Double-Stranded; D019175:DNA Methylation; D004260:DNA Repair; D004195:Disease Models, Animal; D016654:Genes, RAG-1 / Q000235:genetics; D042822:Genomic Instability; D051538:Hepatocyte Nuclear Factor 1-alpha; D006657:Histones / Q000378:metabolism; D008213:Lymphocyte Activation; D008223:Lymphoma / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011995:Recombination, Genetic; D051822:T Cell Transcription Factor 1 / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology*; D060168:Thymocytes / Q000166:cytology; D014178:Translocation, Genetic; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; D051538:Hepatocyte Nuclear Factor 1-alpha; D006657:Histones; C496488:Hnf1a protein, mouse; D051822:T Cell Transcription Factor 1; D051176:beta Catenin
keywords: Ctnnb1; DNA recombination Tcf7; beta-catenin/Tcf-1