Eμ-BRD2 transgenic mice develop B-cell lymphoma and leukemia

Rebecca J. Greenwald, Joseph R. Tumang, Anupama Sinha, Nicolas Currier, Robert Cardiff, Thomas L. Rothstein, Douglas V. Faller, Gerald V. Denis

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1475-1484
Number of pages10
JournalBlood
Volume103
Issue number4
DOIs
StatePublished - Feb 15 2004
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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  • Cite this

    Greenwald, R. J., Tumang, J. R., Sinha, A., Currier, N., Cardiff, R., Rothstein, T. L., Faller, D. V., & Denis, G. V. (2004). Eμ-BRD2 transgenic mice develop B-cell lymphoma and leukemia. Blood, 103(4), 1475-1484. https://doi.org/10.1182/blood-2003-06-2116