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Blood, 15 February 2004, Vol. 103, No. 4, pp. 1475-1484.
Prepublished online as a Blood First Edition Paper on October 16, 2003October 23, 2003; DOI 10.1182/blood-2003-06-2116.
Submitted June 26, 2003
Accepted October 8, 2003
Eµ-BRD2 transgenic mice develop B-cell lymphoma and leukemia
Rebecca J Greenwald, Joseph R Tumang, Anupama Sinha, Nicolas Currier, Robert D Cardiff, Thomas L Rothstein, Douglas V Faller, and Gerald V Denis*
Department of Pathology, Immunology Research Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Immunobiology Unit, Departments of Medicine and Microbiology, Evans Biomedical Research Center, Boston Medical Center, Boston, MA, USA
Cancer Research Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
Center for Comparative Medicine, University of California, Davis, CA, USA
* Corresponding author; email: gdenis{at}bu.edu.
Transgenic mice with lymphoid-restricted overexpression of the double bromodomain protein 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 TAFII250 and the Drosophila homeotic factor female sterile homeotic. Constitutive overexpression 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 some 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 E2Fs and a specific histone acetyltransferase to the cyclin A promoter in both types of transgenic mice 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.
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