Genetic and epigenetic determinants mediate proneness of oncogene breakpoint sites for involvement in TCR translocations

• Published in: Genes and immunity Vol. 15; no. 2; pp. 72 - 81
• Main Authors: Larmonie, N S D, van der Spek, A, Bogers, A J J C, van Dongen, J J M, Langerak, A W
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2014; Nature Publishing Group
• Subjects: 631/208/176; 631/250/1619/554/1775; 631/250/2152/2497; 631/67/395; Acute lymphoblastic leukemia; Adaptor Proteins, Signal Transducing - genetics; Antigen receptors, T cell; Base Sequence; Basic Helix-Loop-Helix Transcription Factors - genetics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Child; Child, Preschool; Chromatin; Chromosome Breakpoints; Chromosome translocations; DNA Breaks, Double-Stranded; DNA damage; DNA Methylation; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Gene Expression; Genes; Homeodomain Proteins - genetics; Human Genetics; Humans; Immunology; Infant; Infant, Newborn; Leukemia; LIM Domain Proteins - genetics; Lymphatic leukemia; Lymphocytes T; Oncogenes; original-article; Physiological aspects; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins c-bcr - genetics; Receptors; Receptors, Antigen, T-Cell - genetics; Sequence Analysis, DNA; T cell receptors; T cells; T-Cell Acute Lymphocytic Leukemia Protein 1; Thoracic surgery; Thymocytes; Thymocytes - cytology; Tlx1 protein; Translocation, Genetic - genetics; V(D)J recombination; V(D)J Recombination - genetics; Netherlands; thymocytes; genetics; TCR translocations; oncogene; epigenetics
• ISSN: 1466-4879; 1476-5470; 1476-5470
• DOI: 10.1038/gene.2013.63

T-cell receptor (TCR) translocations are a genetic hallmark of T-cell acute lymphoblastic leukemia and lead to juxtaposition of oncogene and TCR loci. Oncogene loci become involved in translocations because they are accessible to the V(D)J recombination machinery. Such accessibility is predicted at cryptic recombination signal sequence (cRSS) sites (‘Type 1’) as well as other sites that are subject to DNA double-strand breaks (DSBs) (‘Type 2’) during early stages of thymocyte development. As chromatin accessibility markers have not been analyzed in the context of TCR-associated translocations, various genetic and epigenetic determinants of LMO2 , TAL1 and TLX1 translocation breakpoint (BP) sites and BP cluster regions (BCRs) were examined in human thymocytes to establish DSB proneness and heterogeneity of BP site involvement in TCR translocations. Our data show that DSBs in BCRs are primarily induced in the presence of a genetic element of sequence vulnerability (cRSSs, transposable elements), whereas breaks at single BP sites lacking such elements are more likely induced by chance or perhaps because of patient-specific genetic vulnerability. Vulnerability to obtain DSBs is increased by features that determine chromatin organization, such as methylation status and nucleosome occupancy, although at different levels at different BP sites.