Transgenic mice with lymphoid-restricted overexpression of the double bromodomain protein bromodomain-containing 2 (Brd2) develop splenic B-cell lymphoma and, upon transplantation, B-cell leukemia with leukemic infiltrates in liver and lung. Brd2 is a nuclear-localized transcription factor kinase that is most closely related to TATA box binding protein–associated factor, 250 kDa (TAFII250) and the Drosophila developmental protein female sterile homeotic. Constitutive expression of BRD2 in the lymphoid compartment increases cyclin A transcription, “priming” transgenic B cells for proliferation. Mice stochastically develop an aggressive B-cell lymphoma with the features of B-1 cells, including CD5 and surface IgM expression. The B-cell lymphoma is monoclonal for immunoglobulin gene rearrangement and is phenotypically stable. The lymphoblasts are very large and express a transcriptome that is similar to human non-Hodgkin lymphomas. Both a wild-type BRD2 transgene and a kinase-null point mutant drive lymphomagenesis; therefore we propose that, rather than kinase activity, Brd2-mediated recruitment of E2 promoter binding factors (E2Fs) and a specific histone acetyltransferase to the cyclin A promoter by both types of transgene is a mechanistic basis for neoplasia. This report is the first to describe a transgenic mouse model for constitutive expression of a protein with more than one bromodomain.

中文翻译：

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E-BRD2 转基因小鼠出现 B 细胞淋巴瘤和白血病

具有双溴结构域蛋白含溴结构域 2 (Brd2) 的淋巴限制过表达的转基因小鼠会发展为脾 B 细胞淋巴瘤，并且在移植后会发展为 B 细胞白血病，并在肝脏和肺中出现白血病浸润。Brd2 是一种核定位转录因子激酶，与 TATA 盒结合蛋白相关因子 250 kDa (TAFII250) 和果蝇发育蛋白雌性不育同源基因最密切相关。BRD2 在淋巴区室中的组成型表达增加细胞周期蛋白 A 转录，“启动”转基因 B 细胞的增殖。小鼠随机发展出具有 B-1 细胞特征的侵袭性 B 细胞淋巴瘤，包括 CD5 和表面 IgM 表达。B 细胞淋巴瘤是单克隆免疫球蛋白基因重排，表型稳定。淋巴母细胞非常大并表达类似于人类非霍奇金淋巴瘤的转录组。野生型 BRD2 转基因和激酶无效点突变体均驱动淋巴瘤发生；因此，我们提出，Brd2 介导的 E2 启动子结合因子 (E2Fs) 和特异性组蛋白乙酰转移酶通过两种类型的转基因募集到细胞周期蛋白 A 启动子，而不是激酶活性是肿瘤形成的机制基础。该报告是第一个描述用于组成型表达具有多个溴结构域的蛋白质的转基因小鼠模型的报告。Brd2 介导的 E2 启动子结合因子 (E2Fs) 和特定组蛋白乙酰转移酶通过两种类型的转基因募集到细胞周期蛋白 A 启动子是肿瘤形成的机制基础。该报告是第一个描述用于组成型表达具有多个溴结构域的蛋白质的转基因小鼠模型的报告。Brd2 介导的 E2 启动子结合因子 (E2F) 和特定组蛋白乙酰转移酶通过两种类型的转基因募集到细胞周期蛋白 A 启动子是肿瘤形成的机制基础。该报告是第一个描述用于组成型表达具有多个溴结构域的蛋白质的转基因小鼠模型的报告。