E mu-BRD2 transgenic mice develop B-cell lymphoma and leukemia.
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 (TAF(II)250) 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.
Greenwald
Rebecca J
RJ
Department of Pathology, Immunology Research Division, Brigham and Women's Hospital, Harvard Medcial School, Boston, MA, USA.
Tumang
Joseph R
JR
Sinha
Anupama
A
Currier
Nicolas
N
Cardiff
Robert D
RD
Rothstein
Thomas L
TL
Faller
Douglas V
DV
Denis
Gerald V
GV
D000818:Animals; D000911:Antibodies, Monoclonal; D002868:Chromosomal Proteins, Non-Histone; D019925:Cyclin A / Q000235:genetics; D004195:Disease Models, Animal; D015973:Gene Expression Regulation, Leukemic; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics; D015448:Leukemia, B-Cell / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011994:Recombinant Proteins / Q000235:genetics; D013154:Spleen / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics; D000092468:Bromodomain Containing Proteins
D000911:Antibodies, Monoclonal; D002868:Chromosomal Proteins, Non-Histone; D019925:Cyclin A; D017346:Protein Serine-Threonine Kinases; D011994:Recombinant Proteins; D014157:Transcription Factors; C490844:Brd2 protein, mouse; D000092468:Bromodomain Containing Proteins