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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 23, 2003; DOI 10.1182/blood-2003-06-2116.
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NEOPLASIA
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
From the Department of Pathology, Immunology Research Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Immunobiology Unit, Departments of Medicine and Microbiology, Evans Biomedical Research Center, Boston Medical Center, Boston, MA; Cancer Research Center, Boston University School of Medicine, Boston, MA; and Center for Comparative Medicine, University of California at Davis, Davis, CA.
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.
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