Baron Beverly W, Anastasi John, Montag Anthony, Huo Dezheng, Baron Rebecca M, Karrison Theodore, Thirman Michael J, Subudhi Sumit K, Chin Robert K, Felsher Dean W, Fu Yang-Xin, McKeithan Timothy W, Baron Joseph M
Department of Pathology, Section of Hematology-Oncology, University of Chicago, Chicago, IL 60637, USA.
Proc Natl Acad Sci U S A. 2004 Sep 28;101(39):14198-203. doi: 10.1073/pnas.0406138101. Epub 2004 Sep 16.
BCL6, a gene on chromosome 3, band q27, encodes a zinc finger transcriptional repressor that is needed for germinal center formation and has been implicated in the pathogenesis of some human lymphomas when it is mutated or involved in chromosomal rearrangements. To explore further the mechanisms of action of BCL6 in lymphomagenesis, we developed a transgenic mouse model mimicking a common translocation, the t(3, 14)(q27;q32), in human lymphomas. The transgenic mice develop normally and express the transgenic BCL6 protein constitutively in lymphocytes. A small fraction of the animals develop B and T cell lymphomas after a long latency period, but the incidence is dramatically enhanced following administration of N-ethyl-N-nitrosourea, a carcinogen that induces DNA mutations. The N-ethyl-N-nitrosourea-induced lymphomas spread widely, were exclusively T cell, expressed the BCL6 protein, and occurred only in the transgenic mice. Because BCL6 expression has been reported in a number of T cell tumors as well as in the more commonly occurring B cell lymphomas in humans, our transgenic mice provide a model for the study of human lymphomas.
BCL6基因位于3号染色体q27带，编码一种锌指转录抑制因子，生发中心的形成需要该因子，当它发生突变或参与染色体重排时，与一些人类淋巴瘤的发病机制有关。为了进一步探究BCL6在淋巴瘤发生中的作用机制，我们构建了一种转基因小鼠模型，模拟人类淋巴瘤中常见的t(3, 14)(q27;q32)易位。转基因小鼠发育正常，淋巴细胞中持续表达转基因BCL6蛋白。一小部分动物在长时间潜伏期后发生B细胞和T细胞淋巴瘤，但在给予N-乙基-N-亚硝基脲（一种诱导DNA突变的致癌物）后，发病率显著提高。N-乙基-N-亚硝基脲诱导的淋巴瘤广泛扩散，均为T细胞淋巴瘤，表达BCL6蛋白，且仅发生在转基因小鼠中。由于在许多T细胞肿瘤以及人类中更常见的B细胞淋巴瘤中都有BCL6表达的报道，我们的转基因小鼠为研究人类淋巴瘤提供了一个模型。
