Howard Hughes Medical Institute, Children's Hospital, Immune Disease Institute, and Harvard Medical School, Boston, MA 02115, USA.
J Exp Med. 2010 Jul 5;207(7):1369-80. doi: 10.1084/jem.20100285. Epub 2010 Jun 21.
Ataxia telangiectasia mutated (ATM) deficiency predisposes humans and mice to T lineage lymphomas with recurrent chromosome 14 translocations involving the T cell receptor alpha/delta (Tcra/d) locus. Such translocations have been thought to result from aberrant repair of DNA double-strand breaks (DSBs) during Tcra locus V(D)J recombination, and to require the Tcra enhancer (Ealpha) for Tcra rearrangement or expression of the translocated oncogene. We now show that, in addition to the known chromosome 14 translocation, ATM-deficient mouse thymic lymphomas routinely contain a centromeric fragment of chromosome 14 that spans up to the 5' boundary of the Tcra/d locus, at which position a 500-kb or larger region centromeric to Tcra/d is routinely amplified. In addition, they routinely contain a large deletion of the telomeric end of one copy of chromosome 12. In contrast to prior expectations, the recurrent translocations and amplifications involve V(D)J recombination-initiated breaks in the Tcrd locus, as opposed to the Tcra locus, and arise independently of the Ealpha. Overall, our studies reveal previously unexpected mechanisms that contribute to the oncogenic transformation of ATM-deficient T lineage cells.
共济失调毛细血管扩张突变基因（ATM）缺陷使人类和小鼠易患 T 细胞谱系淋巴瘤，其特征是染色体 14 频繁易位，涉及 T 细胞受体 alpha/delta（Tcra/d）基因座。这些易位被认为是由于 Tcra 基因座 V(D)J 重组过程中 DNA 双链断裂（DSBs）的异常修复所致，并且需要 Tcra 增强子（Ealpha）来进行 Tcra 重排或易位癌基因的表达。我们现在表明，除了已知的染色体 14 易位外，ATM 缺陷型小鼠胸腺淋巴瘤通常包含染色体 14 的着丝粒片段，该片段可延伸至 Tcra/d 基因座的 5' 边界，在该位置，Tcra/d 基因座的着丝粒侧可扩增至 500kb 或更大的区域。此外，它们通常还包含一条 12 号染色体末端的大片段缺失。与先前的预期相反，这些频繁的易位和扩增涉及 Tcrd 基因座而非 Tcra 基因座中 V(D)J 重组起始的断裂，并且独立于 Ealpha 发生。总体而言，我们的研究揭示了先前未预料到的机制，这些机制有助于 ATM 缺陷型 T 细胞谱系细胞的致癌转化。
