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

Genes & Immunity volume 15, pages 72–81 (2014)Cite this article

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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.

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Acknowledgements

This study was supported by Mozaïek (Mosaic) Grant 017.004.089 from The Netherlands Organization for Scientific Research (NWO) to NSDL. We thank Dr Menno C van Zelm and Dr Willem A. Dik for critically reading the manuscript; Lisa Caesar and Andrea Jessen for their help with the initial experiments; and Sandra de Bruijn-Versteeg for preparing figures. The studies were performed in the department of Immunology (head: Professor H Hooijkaas) as part of the Molecular Medicine Postgraduate School of the Erasmus MC, Rotterdam, The Netherlands.

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Authors and Affiliations

  1. Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    N S D Larmonie, A van der Spek, J J M van Dongen & A W Langerak

  2. Department of Cardio-thoracic Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    A J J C Bogers

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  1. N S D Larmonie
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Correspondence to A W Langerak.

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Larmonie, N., van der Spek, A., Bogers, A. et al. Genetic and epigenetic determinants mediate proneness of oncogene breakpoint sites for involvement in TCR translocations. Genes Immun 15, 72–81 (2014). https://doi.org/10.1038/gene.2013.63

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