Breit T M, Wolvers-Tettero I L, van Dongen J J
Department of Immunology, University Hospital Dijkzigt/Erasmus University, Rotterdam, The Netherlands.
Oncogene. 1994 Jul;9(7):1847-53.
tal-1 deletions are caused by a site specific recombination, which exclusively occurs in 12-26% of T-cell acute lymphoblastic leukemias (T-ALL). In a previous study on a large series of T-ALL we demonstrated an apparent preferential occurrence of tal-1 deletions in CD3- and CD3+ alpha beta lineage T-ALL with TcR-delta gene deletions on one or both alleles. In the present study we investigated whether accessibility of the tal-1 deletion breakpoint regions influences the preferential occurrence in specific T-ALL subgroups. Because DNA methylation is assumed to determine accessibility of DNA for recombination, the methylation status of the tal-1 deletion type 1 breakpoint regions (sildb and taldb1) was studied. Although the sildb were completely demethylated in all T-ALL, preferential (de)methylation configurations of the taldb1 were observed in the analysed 119 T-ALL. Most TcR-alpha beta + T-ALL contained completely demethylated taldb1 (77%), whereas in most TcR-gamma delta + T-ALL partial or complete methylation occurred (42% and 47%, respectively). In T-ALL subgroups defined by different TcR-delta gene configurations also preferential taldb1 (de)methylation patterns were seen, which was most prominent in T-ALL with both TcR-delta genes deleted (84% complete demethylation). The previously observed preferential occurrence of tal-1 deletion type 1 in TcR-alpha beta + vs CD3- T-ALL and in T-ALL with both vs one TcR-delta genes deleted, disappeared when we retricted to T-ALL with completely demethylated taldb1. Moreover, all T-ALL with a tal-1 deletion type 1 (n = 15) contained completely demethylated taldb1. We therefore conclude that complete demethylation of taldb1 is a prerequisite for tal-1 deletions type 1 and that the differences in tal-1 deletion frequencies observed in the various T-ALL subgroups are caused by differences in the (de)methylation status of taldb1 in these subgroups.
tal-1缺失是由位点特异性重组引起的，这种重组仅在12% - 26%的T细胞急性淋巴细胞白血病（T-ALL）中出现。在之前一项针对大量T-ALL病例的研究中，我们发现tal-1缺失在CD3 - 和CD3 + αβ谱系T-ALL中明显更易发生，且这些病例的一个或两个等位基因存在TcR-δ基因缺失。在本研究中，我们调查了tal-1缺失断点区域的可及性是否会影响其在特定T-ALL亚组中的优先发生情况。由于DNA甲基化被认为决定了DNA重组的可及性，因此我们研究了tal-1缺失1型断点区域（sildb和taldb1）的甲基化状态。尽管在所有T-ALL中sildb均完全去甲基化，但在分析的119例T-ALL中观察到了taldb1的优先（去）甲基化构型。大多数TcR-αβ + T-ALL的taldb1完全去甲基化（77%），而在大多数TcR-γδ + T-ALL中则发生部分或完全甲基化（分别为42%和47%）。在由不同TcR-δ基因构型定义的T-ALL亚组中也观察到了优先的taldb1（去）甲基化模式，这在两个TcR-δ基因均缺失的T-ALL中最为显著（84%完全去甲基化）。当我们将研究局限于taldb1完全去甲基化的T-ALL时，之前观察到的tal-1缺失1型在TcR-αβ + 与CD3 - T-ALL之间以及两个与一个TcR-δ基因缺失的T-ALL之间的优先发生情况消失了。此外，所有具有tal-1缺失1型的T-ALL（n = 15）的taldb1均完全去甲基化。因此，我们得出结论，taldb1的完全去甲基化是tal-1缺失1型的先决条件，并且在各种T-ALL亚组中观察到的tal-1缺失频率差异是由这些亚组中taldb1的（去）甲基化状态差异所导致的。
