Haploinsufficiency identifies STAT5 as a modifier of IL-7-induced lymphomas
Haploinsufficiency identifies STAT5 as a modifier of IL-7-induced lymphomas
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DOI：
10.1038/sj.onc.1208726
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发表时间：
2005-08-01
期刊：
影响因子：
8
通讯作者：
Goldsmith, MA
中科院分区：
文献类型：
--
作者：
Abraham, N;Ma, MC;Goldsmith, MA
在由白细胞介素-7（IL-7）诱导的淋巴瘤发展模型中，从遗传学角度评估了对受体组分和信号传导效应子、信号转导子和转录激活子（STAT）5A/5 B的需求。这种T-和B-细胞祖细胞和成熟淋巴细胞的生长因子激活存活和增殖途径，包括Bcl-2，磷脂酰肌醇-3激酶和STAT 5。体内IL-7的过表达导致淋巴瘤发展的早期死亡。与野生型小鼠相比，IL-7 R α亚基杂合的过表达IL-7的小鼠显示出改善的存活率。此外，具有STAT 5A和STAT 5 B中的每一个靶向等位基因的STAT 5A/5 B（+/-）复合杂合小鼠显示出IL-7诱导的死亡率和疾病发展的显著改善。STAT 5A/5 B（+/-）复合杂合子小鼠在干细胞和淋巴细胞发育和细胞结构方面是正常的。较低的STAT 5蛋白水平伴随着STAT 5A/5 B拷贝数的减少，这表明STAT 5单倍不足是IL-7信号强度的调节剂。
The requirement for receptor components and the signalling effector, signal transducer and activator of transcription (STAT) 5A/5B, was assessed genetically in a lymphoma development model induced by interleukin-7 (IL-7). This growth factor for T- and B-cell progenitors and mature lymphocytes activates survival and proliferative pathways including Bcl-2, phosphatidylinositol-3 kinase and STAT5. Overexpression of IL-7 in vivo causes early mortality from lymphoma development. Mice overexpressing IL-7 that were heterozygous for the IL-7R alpha subunit showed improved survival compared to wild-type mice. In addition, STAT5A/5B(+/-) compound heterozygous mice with one targeted allele each of STAT5A and STAT5B showed striking amelioration of IL-7-induced mortality and disease development. STAT5A/5B(+/-) compound heterozygous mice were otherwise normal in stem cell and lymphocyte development and cellularity. Lower STAT5 protein levels accompanied the reduction in STAT5A/5B copy number, which suggests that STAT5 haploinsufficiency is a modifier of IL-7 signal strength.