title: A transgenic mouse model demonstrating the oncogenic role of mutations in the polycomb-group gene EZH2 in lymphomagenesis.
abstract: 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 EZH2(Y641F) 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 EZH2(Y641F) 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 EZH2(Y641F). 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, EZH2(Y641F) 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.
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Medicine, Hematology and Oncology, University of Frankfurt, Frankfurt/Main, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Tobias
authors.initials: T
authors.lastname: Berg
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Silvia
authors.initials: S
authors.lastname: Thoene
authors.affiliation: Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada;
authors.forename: Damian
authors.initials: D
authors.lastname: Yap
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Tracee
authors.initials: T
authors.lastname: Wee
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada; Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany;
authors.forename: Nathalie
authors.initials: N
authors.lastname: Schoeler
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Patty
authors.initials: P
authors.lastname: Rosten
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Emilia
authors.initials: E
authors.lastname: Lim
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Misha
authors.initials: M
authors.lastname: Bilenky
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Mungall
authors.affiliation: Department of Medicine, Hematology and Oncology, University of Frankfurt, Frankfurt/Main, Germany;
authors.forename: Thomas
authors.initials: T
authors.lastname: Oellerich
authors.affiliation: Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Medicine, University of British Columbia, Vancouver, BC, Canada;
authors.forename: Sherry
authors.initials: S
authors.lastname: Lee
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Courteney K
authors.initials: CK
authors.lastname: Lai
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Patricia
authors.initials: P
authors.lastname: Umlandt
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Anisa
authors.initials: A
authors.lastname: Salmi
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Harry
authors.initials: H
authors.lastname: Chang
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: Lisa
authors.initials: L
authors.lastname: Yue
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: David
authors.initials: D
authors.lastname: Lai
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada;
authors.forename: S-W Grace
authors.initials: SW
authors.lastname: Cheng
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada; Simon Fraser University, Burnaby, BC, Canada;
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Morin
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Microbiology and Immunology and.
authors.forename: Martin
authors.initials: M
authors.lastname: Hirst
authors.affiliation: Department of Medicine, Hematology and Oncology, University of Frankfurt, Frankfurt/Main, Germany;
authors.forename: Hubert
authors.initials: H
authors.lastname: Serve
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; and.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; and.
authors.forename: Gregg B
authors.initials: GB
authors.lastname: Morin
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.affiliation: Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada;
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Aparicio
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Medicine, University of British Columbia, Vancouver, BC, Canada;
authors.forename: R Keith
authors.initials: RK
authors.lastname: Humphries
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006657:Histones / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008223:Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008239:Lysine / Q000378:metabolism; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D013154:Spleen / Q000378:metabolism / Q000473:pathology
chemical_list: D006657:Histones; D016271:Proto-Oncogene Proteins c-myc; D063151:Polycomb Repressive Complex 2; D008239:Lysine