No abstract

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. B CL6, a gene on chromosome 3, band q27, was identified by us and others through its involvement in chromosomal rearrangements associated with a variety of non-Hodgkin lymphomas, especially diffuse large-cell B cell lymphomas (1, 2). The breakpoints cluster around the first (noncoding) exon of BCL6 (2), and it is thought that BCL6 expression becomes deregulated in Ϸ40% of diffuse large-cell B cell lymphomas by rearrangements in which normal BCL6 regulatory sequences are replaced by heterologous promoters (3). Additionally, in other lymphomas, mutations occur that affect BCL6 binding sites in the first (noncoding) exon and interfere with autoregulation (4). The BCL6 gene encodes a nuclear zinc finger protein, a transcriptional repressor, needed for germinal center formation (5). This protein is expressed at high levels in human lymphoid germinal center B cells, most cortical thymocytes, and some B and T cell lymphomas, but is not expressed in pre-or postgerminal center B cells or plasma cells (6).The production of transgenic mice expressing human BCL6 has not been reported previously. It is postulated that the reason it is difficult to generate such mice by using conventional constructs is that they die during embryogenesis. We were able to generate BCL6 transgenic mice expressing human BCL6 specifically in lymphocytes in a two-mouse model that mimics a common translocation, the t(3,14)(q27;q32), seen in human lymphomas. We report the development of T cell lymphomas in a significant fraction of these mice after the administration of the carcinogen N-ethyl-N-nitrosourea (ENU). Materials and Methods BCL6 Transgenic Lines.We used an approach similar to that of Felsher and Bishop (7) to generate mice that express the human BCL6 transgene selectively in lymphocytes. This system requires two kinds of transgenic mice. The first, obtained from Felsher and Bishop, expresses the tetracycline-tra...