A transgenic mouse model demonstrating the oncogenic role of mutations in the polycomb-group gene EZH2 in lymphomagenesis

• Published in: Blood 2014-06, Vol.123 (25), p.3914-3924
• Main Authors: Berg, Tobias, Thoene, Silvia, Yap, Damian, Wee, Tracee, Schoeler, Nathalie, Rosten, Patty, Lim, Emilia, Bilenky, Misha, Mungall, Andrew J., Oellerich, Thomas, Lee, Sherry, Lai, Courteney K., Umlandt, Patricia, Salmi, Anisa, Chang, Harry, Yue, Lisa, Lai, David, Cheng, S.-W. Grace, Morin, Ryan D., Hirst, Martin, Serve, Hubert, Marra, Marco A., Morin, Gregg B., Gascoyne, Randy D., Aparicio, Samuel A., Humphries, R. Keith
• Format: Article
• Language: English
• Subjects: Animals; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; Blotting, Western; Bone Marrow Cells - metabolism; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Disease Models, Animal; Female; Flow Cytometry; Gene Expression Profiling; Histones - metabolism; Humans; Kaplan-Meier Estimate; Lymphoma - genetics; Lymphoma - metabolism; Lymphoma - pathology; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - metabolism; Lymphoma, B-Cell - pathology; Lysine - metabolism; Male; Methylation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Polycomb Repressive Complex 2 - genetics; Polycomb Repressive Complex 2 - metabolism; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Spleen - metabolism; Spleen - pathology
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2012-12-473439

The histone methyltransferase EZH2 is frequently mutated in germinal center–derived diffuse large B-cell lymphoma and follicular lymphoma. To further characterize these EZH2 mutations in lymphomagenesis, we generated a mouse line where EZH2Y641F is expressed from a lymphocyte-specific promoter. Spleen cells isolated from the transgenic mice displayed a global increase in trimethylated H3K27, but the mice did not show an increased tendency to develop lymphoma. As EZH2 mutations often coincide with other mutations in lymphoma, we combined the expression of EZH2Y641F by crossing these transgenic mice with Eµ-Myc transgenic mice. We observed a dramatic acceleration of lymphoma development in this combination model of Myc and EZH2Y641F. The lymphomas show histologic features of high-grade disease with a shift toward a more mature B-cell phenotype, increased cycling and gene expression, and epigenetic changes involving important pathways in B-cell regulation and function. Furthermore, they initiate disease in secondary recipients. In summary, EZH2Y641F can collaborate with Myc to accelerate lymphomagenesis demonstrating a cooperative role of EZH2 mutations in oncogenesis. This murine lymphoma model provides a new tool to study global changes in the epigenome caused by this frequent mutation and a promising model system for testing novel treatments. •A functional demonstration of the oncogenic role of mutated EZH2 in a mouse model is presented.•The global effects of mutated EZH2 on expression and epigenome have been characterized.