Perturbation of lkaros isoform selection by MLV integration is a cooperative event in NotchIC-induced T cell leukemogenesis
Perturbation of lkaros isoform selection by MLV integration is a cooperative event in NotchIC-induced T cell leukemogenesis
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DOI：
10.1016/s1535-6108(03)00137-5
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发表时间：
2003-06-01
期刊：
影响因子：
50.3
通讯作者：
Capobianco, AJ
中科院分区：
文献类型：
--
作者：
Beverly, LJ;Capobianco, AJ
人 T 细胞急性淋巴细胞白血病 (T-ALL) 中的染色体易位 t(7;9)(q34;q34.3) 导致 Notch (N-ic) 胞内结构域的异常表达。与当前肿瘤发生的多步骤模型一致，在 T 细胞祖细胞中表达 N-ic 的小鼠会发展出潜伏期延长的 T-ALL 样疾病。前病毒插入突变极大地加速了 N-ic 转基因小鼠白血病的发病。我们证明 Ikaros (Ik) 位点是 N-ic 转基因小鼠中原病毒整合的常见目标，这会通过改变同种型表达而导致 Ik DNA 结合活性的丧失。我们认为协同白血病发生发生在具有组成型 N-ic 和改变的 Ik 亚型表达的细胞中，因为通常被 Ik 抑制的基因被 N-ic/CSL 激活。
The chromosomal translocation t(7;9)(q34;q34.3) in human T cell acute lymphoblastic leukemia (T-ALL) results in the aberrant expression of the intracellular domain of Notch (N-ic). Consistent with the current multistep model for tumorigenesis, mice that express N-ic in T cell progenitors develop a T-ALL-like disease with a lengthened latency. Proviral insertional mutagenesis greatly accelerated the onset of leukemia in N-ic transgenic mice. We demonstrate that the Ikaros (Ik) locus is a common target of proviral integration in N-ic transgenic mice, which results in the loss of Ik DNA binding activity through altered isoform expression. We propose that cooperative leukemogenesis occurs in cells that have constitutive N-ic and altered Ik isoform expression because genes normally repressed by Ik become activated by N-ic/CSL.