Eμ-BRD2 transgenic mice develop B-cell lymphoma and leukemia
Eμ-BRD2 transgenic mice develop B-cell lymphoma and leukemia
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DOI：
10.1182/blood-2003-06-2116
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发表时间：
2004-02-15
期刊：
影响因子：
20.3
通讯作者：
Denis, GV
中科院分区：
文献类型：
--
作者：
Greenwald, RJ;Tumang, JR;Denis, GV
具有双溴结构域蛋白含溴结构域2（Brd 2）的淋巴限制性过表达的转基因小鼠发展脾B细胞淋巴瘤，并且在移植后发展肝和肺中的B细胞白血病伴白血病浸润。Brd 2是一种核定位的转录因子激酶，与TATA盒结合蛋白相关因子250 kDa（TAF（II）250）和果蝇发育蛋白雌性不育同源异型物最密切相关。BRD 2在淋巴区室中的组成型表达增加了细胞周期蛋白A的转录，“引发”转基因B细胞增殖。小鼠随机发生具有B-1细胞特征的侵袭性B细胞淋巴瘤，包括CD 5和表面IgM表达。B细胞淋巴瘤是免疫球蛋白基因重排的单克隆，并且表型稳定。淋巴母细胞非常大，并表达与人类非霍奇金淋巴瘤相似的转录组。野生型BRD 2转基因和激酶空点突变体驱动淋巴瘤发生，因此，我们建议，而不是激酶活性，Brd 2介导的招聘E2启动子结合因子（E2 Fs）和特定的组蛋白乙酰转移酶的细胞周期蛋白A启动子的两种类型的转基因是一个机制的基础瘤。这份报告是第一个描述一个转基因小鼠模型的组成型表达的蛋白质与一个以上的溴结构域。
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 (TAF(II)250) 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.