title: Genetic and epigenetic determinants mediate proneness of oncogene breakpoint sites for involvement in TCR translocations.
abstract: 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.
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: N S D
authors.initials: NS
authors.lastname: Larmonie
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: van der Spek
authors.affiliation: Department of Cardio-thoracic Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: A J J C
authors.initials: AJ
authors.lastname: Bogers
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: J J M
authors.initials: JJ
authors.lastname: van Dongen
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: A W
authors.initials: AW
authors.lastname: Langerak
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D056905:Chromosome Breakpoints; D053903:DNA Breaks, Double-Stranded; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D060588:LIM Domain Proteins / Q000235:genetics*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051562:Proto-Oncogene Proteins c-bcr / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D017422:Sequence Analysis, DNA; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D060168:Thymocytes / Q000166:cytology; D014178:Translocation, Genetic / Q000235:genetics; D060152:V(D)J Recombination / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; D011518:Proto-Oncogene Proteins; D051562:Proto-Oncogene Proteins c-bcr; D011948:Receptors, Antigen, T-Cell; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C085117:LMO2 protein, human; C067143:TAL1 protein, human; C071250:TLX1 protein, human; C496613:BCR protein, human