Larmonie N S D, van der Spek A, Bogers A J J C, van Dongen J J M, Langerak A W
Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Department of Cardio-thoracic Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Genes Immun. 2014 Mar;15(2):72-81. doi: 10.1038/gene.2013.63. Epub 2013 Dec 5.
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.
T细胞受体（TCR）易位是T细胞急性淋巴细胞白血病的一个遗传特征，会导致致癌基因与TCR基因座并列。致癌基因座参与易位是因为V（D）J重组机制可作用于它们。在胸腺细胞发育早期，在隐蔽重组信号序列（cRSS）位点（“1型”）以及其他会发生DNA双链断裂（DSB）的位点（“2型”）预计会出现这种可及性。由于尚未在TCR相关易位的背景下分析染色质可及性标记，因此在人类胸腺细胞中研究了LMO2、TAL1和TLX1易位断点（BP）位点及BP簇区域（BCR）的各种遗传和表观遗传决定因素，以确定DSB倾向以及BP位点参与TCR易位的异质性。我们的数据表明，BCR中的DSB主要是在存在序列易损性遗传元件（cRSS、转座元件）的情况下诱导产生的，而缺乏此类元件的单个BP位点处的断裂更可能是偶然诱导的，或者可能是由于患者特异性的遗传易损性。决定染色质组织的特征（如甲基化状态和核小体占有率）会增加获得DSB的易感性，尽管在不同的BP位点其程度不同。
