Perturbation of B and T cell development and predisposition to lymphomagenesis in E mu Bmi1 transgenic mice require the Bmi1 RING finger
Perturbation of B and T cell development and predisposition to lymphomagenesis in E mu Bmi1 transgenic mice require the Bmi1 RING finger
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DOI：
10.1038/sj.onc.1201262
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发表时间：
1997-08-21
期刊：
影响因子：
8
通讯作者：
Berns, A
中科院分区：
文献类型：
--
作者：
Alkema, MJ;Jacobs, H;Berns, A
Bmi1基因的前病毒激活暗示Bmi1在淋巴瘤发生中是c-Myc的合作者。为了确定Bmi1过表达对造血和淋巴瘤形成的影响，在其淋巴细胞室中产生了过表达不同形式Bmi1蛋白的转基因小鼠。过度表达野生型Bmi1蛋白的E mu Bmi1转基因小鼠淋巴细胞发育受到干扰，对B细胞和T细胞淋巴瘤发生高度敏感。Bmi1蛋白的突变分析表明，保守的n端环指和Bmi1的中心部分对其致癌潜力至关重要，而c端富含Pro-Ser的区域则不是必需的。我们在E mu Bmi1小鼠中使用原病毒标记来识别与Bmi1合作的淋巴瘤发生基因。转基因E mu Bmi1小鼠的MoMLV感染加速了淋巴瘤的发展。在这些肿瘤中经常观察到Pim和Myc基因的前病毒激活，而不是Gfi1基因。这些结果表明Bmi1是一个强有力的致癌基因，并提示它在早期淋巴细胞发育中起重要作用。
Proviral activation of the Bmi1 gene has implicated Bmi1 as a collaborator of c-Myc in lymphomagenesis. To determine the effect of Bmi1 overexpression on hematopoiesis and lymphomagenesis transgenic mice were generated that overexpress different forms of the Bmi1 protein in their lymphoid compartment. E mu Bmi1 transgenic mice, overexpressing the wild type Bmi1 protein showed a perturbed lymphoid development and were highly susceptible to B and T cell lymphomagenesis. Mutational analysis of the Bmi1 protein demonstrated that the conserved N-terminal RING finger and central part of Bmi1 are essential for its oncogenic potential whereas the C-terminal Pro-Ser rich region is not required. We have used provirus tagging in the E mu Bmi1 mice to identify genes that cooperate with Bmi1 in lymphomagenesis. MoMLV infection in E mu Bmi1 transgenic mice accelerated Lymphoma development. Proviral activation of the Pim and Myc genes but not the Gfi1 gene were frequently observed in these tumors. These results demonstrate that Bmi1 is a potent oncogene and suggest that it plays an important role in early lymphoid development.