The RAG-1/2 endonuclease causes genomic instability and controls CNS complications of lymphoblastic leukemia in p53/Prkdc-deficient mice
The RAG-1/2 endonuclease causes genomic instability and controls CNS complications of lymphoblastic leukemia in p53/Prkdc-deficient mice
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DOI：
10.1016/s1535-6108(02)00236-2
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发表时间：
2003-01-01
期刊：
影响因子：
50.3
通讯作者：
Danska, JS
中科院分区：
文献类型：
--
作者：
Gladdy, RA;Taylor, MD;Danska, JS
双链DNA断裂（DSB）诱导细胞培养中的染色体易位和基因扩增，但DSB引起体内基因组不稳定性的机制知之甚少。我们表明，RAG-1/2诱导的DSB导致IgH/c-Myc易位白血病pro-Ell细胞从p53/Prkdc缺陷小鼠。引人注目的是，这些易位是复杂的，克隆异质性和扩增。我们观察到重复IgH/c-Myc融合双着丝粒染色体，表明扩增发生的重复循环的桥梁，断裂和融合。在RAG-2/p53/Prkdc缺陷小鼠中白血病发生没有减轻，但白血病pro-B细胞缺乏IgH/c-Myc易位。因此，p53/Prkdc破坏赋予的全局基因组不稳定性有效地转化了缺乏RAG-1/2诱导的DSB的pro-B细胞。出乎意料的是，RAG-2/p53/Prkdc缺陷小鼠也发生了软脑膜白血病，为这种人类淋巴母细胞恶性肿瘤的常见并发症提供了一种新的自发模型。
Double-strand DNA breaks (DSB) induce chromosomal translocations and gene amplification in cell culture, but mechanisms by which DSB cause genomic instability in vivo are poorly understood. We show that RAG-1/2-induced DSB cause IgH/c-Myc translocations in leukemic pro-Ell cells from p53/Prkdc-deficient mice. Strikingly, these translocations were complex, clonally heterogeneous and amplified. We observed reiterated IgH/c-Myc fusions on dicentric chromosomes, suggesting that amplification occurred by repeated cycles of bridge, breakage and fusion. Leukemogenesis was not mitigated in RAG-2/p53/Prkdc-deficient mice, but leukemic pro-B cells lacked IgH/c-Myc translocations. Thus, global genomic instability conferred by p53/Prkdc disruption efficiently transforms pro-B cells lacking RAG-1/2-induced DSB. Unexpectedly, RAG-2/p53/Prkdc-deficient mice also developed leptomeningeal leukemia, providing a novel spontaneous model for this frequent complication of human lymphoblastic malignancies.