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

Blood - Tập 123 Số 25 - Trang 3914-3924 - 2014
Tobias Berg1,2,3,4, Silvia Thoene4, Damian Yap5,6, Tracee Wee4, Nathalie Schoeler7,8,4, Patty Rosten4, Emilia L. Lim9, Misha Bilenky9, Andrew J. Mungall9, Thomas Oellerich1, Sherry Lee10,6, Courteney K. Lai4, Patricia Umlandt4, Anisa Salmi4, Harry Chang4, Lisa Yue4, David Lai4, S.‐W. Grace Cheng9, Ryan D. Morin9,11, Martin Hirst9,12, Hubert Serve1, Marco A. Marra9,13, Gregg B. Morin9,13, Randy D. Gascoyne14,5, Samuel Aparício5,6, R. Keith Humphries10,4
1Department of Medicine, Hematology and Oncology, University of Frankfurt, Frankfurt/Main, Germany;
2German Cancer Consortium (DKTK), Heidelberg, Germany
3German cancer Research Center (DKFZ), Heidelberg, Germany
4Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada;
5Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
6Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada;
7Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
8Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
9Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada
10Department of Medicine, University of British Columbia, Vancouver, BC, Canada
11Simon Fraser University, Burnaby, BC, Canada
12Department of Microbiology and Immunology and
13Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; and
14Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada

Tóm tắt

Key Points 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.

Từ khóa


Tài liệu tham khảo

Cao, 2002, Role of histone H3 lysine 27 methylation in Polycomb-group silencing., Science, 298, 1039, 10.1126/science.1076997

Sauvageau, 2010, Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer., Cell Stem Cell, 7, 299, 10.1016/j.stem.2010.08.002

O’Carroll, 2001, The polycomb-group gene Ezh2 is required for early mouse development., Mol Cell Biol, 21, 4330, 10.1128/MCB.21.13.4330-4336.2001

Margueron, 2008, Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms., Mol Cell, 32, 503, 10.1016/j.molcel.2008.11.004

Su, 2003, Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement., Nat Immunol, 4, 124, 10.1038/ni876

Raaphorst, 2000, Cutting edge: polycomb gene expression patterns reflect distinct B cell differentiation stages in human germinal centers., J Immunol, 164, 1, 10.4049/jimmunol.164.1.1

van Galen, 2004, Distinct expression patterns of polycomb oncoproteins and their binding partners during the germinal center reaction., Eur J Immunol, 34, 1870, 10.1002/eji.200424985

Varambally, 2002, The polycomb group protein EZH2 is involved in progression of prostate cancer., Nature, 419, 624, 10.1038/nature01075

Kamminga, 2006, The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion., Blood, 107, 2170, 10.1182/blood-2005-09-3585

Herrera-Merchan, 2012, Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease., Nature Commun, 623

Suvà, 2009, EZH2 is essential for glioblastoma cancer stem cell maintenance., Cancer Res, 69, 9211, 10.1158/0008-5472.CAN-09-1622

van Kemenade, 2001, Coexpression of BMI-1 and EZH2 polycomb-group proteins is associated with cycling cells and degree of malignancy in B-cell non-Hodgkin lymphoma., Blood, 97, 3896, 10.1182/blood.V97.12.3896

Dukers, 2004, Unique polycomb gene expression pattern in Hodgkin’s lymphoma and Hodgkin’s lymphoma-derived cell lines., Am J Pathol, 164, 873, 10.1016/S0002-9440(10)63175-6

Raaphorst, 2000, Coexpression of BMI-1 and EZH2 polycomb group genes in Reed-Sternberg cells of Hodgkin’s disease., Am J Pathol, 157, 709, 10.1016/S0002-9440(10)64583-X

Morin, 2010, Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin., Nat Genet, 42, 181, 10.1038/ng.518

McCabe, 2012, Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27)., Proc Natl Acad Sci USA, 109, 2989, 10.1073/pnas.1116418109

Pasqualucci, 2011, Inactivating mutations of acetyltransferase genes in B-cell lymphoma., Nature, 471, 189, 10.1038/nature09730

Morin, 2011, Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma., Nature, 476, 298, 10.1038/nature10351

Sneeringer, 2010, Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas., Proc Natl Acad Sci USA, 107, 20980, 10.1073/pnas.1012525107

Yap, 2011, Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation., Blood, 117, 2451, 10.1182/blood-2010-11-321208

McCabe, 2012, EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations., Nature, 492, 108, 10.1038/nature11606

Knutson, 2012, A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells., Nat Chem Biol, 8, 890, 10.1038/nchembio.1084

Konze, 2013, An orally bioavailable chemical probe of the lysine methyltransferases EZH2 and EZH1., ACS Chem Biol, 8, 1324, 10.1021/cb400133j

Qi, 2012, Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation., Proc Natl Acad Sci USA, 109, 21360, 10.1073/pnas.1210371110

Pineault, 2003, Induction of acute myeloid leukemia in mice by the human leukemia-specific fusion gene NUP98-HOXD13 in concert with Meis1., Blood, 101, 4529, 10.1182/blood-2002-08-2484

Bichi, 2002, Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression., Proc Natl Acad Sci USA, 99, 6955, 10.1073/pnas.102181599

Iritani, 1999, Distinct signals mediate maturation and allelic exclusion in lymphocyte progenitors., Immunity, 10, 713, 10.1016/S1074-7613(00)80070-9

Ryan, 2011, EZH2 codon 641 mutations are common in BCL2-rearranged germinal center B cell lymphomas., PLoS ONE, 6, e28585, 10.1371/journal.pone.0028585

Velichutina, 2010, EZH2-mediated epigenetic silencing in germinal center B cells contributes to proliferation and lymphomagenesis., Blood, 116, 5247, 10.1182/blood-2010-04-280149

Béguelin, 2013, EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation., Cancer Cell, 23, 677, 10.1016/j.ccr.2013.04.011

Johnson, 2009, Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival., Blood, 114, 2273, 10.1182/blood-2009-03-212191

Gunster, 2001, Differential expression of human Polycomb group proteins in various tissues and cell types., J Cell Biochem, 81, 129, 10.1002/jcb.1093

Bracken, 2003, EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer., EMBO J, 22, 5323, 10.1093/emboj/cdg542

Yan, 2013, EZH2 overexpression in natural killer/T-cell lymphoma confers growth advantage independently of histone methyltransferase activity., Blood, 121, 4512, 10.1182/blood-2012-08-450494

Haupt, 1993, bmi-1 transgene induces lymphomas and collaborates with myc in tumorigenesis., Oncogene, 8, 3161

Jacobs, 1999, Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF., Genes Dev, 13, 2678, 10.1101/gad.13.20.2678

Scott, 2007, Role of the chromobox protein CBX7 in lymphomagenesis., Proc Natl Acad Sci USA, 104, 5389, 10.1073/pnas.0608721104

Lee, 2013, Polycomb repressive complex 2 (PRC2) suppresses Eμ-myc lymphoma., Blood, 122, 2654, 10.1182/blood-2013-02-484055

Cromer, 2012, Identification of somatic mutations in parathyroid tumors using whole-exome sequencing., J Clin Endocrinol Metab, 97, E1774, 10.1210/jc.2012-1743

Ernst, 2010, Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders., Nat Genet, 42, 722, 10.1038/ng.621

Nikoloski, 2010, Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes., Nat Genet, 42, 665, 10.1038/ng.620

Simon, 2012, A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia., Genes Dev, 26, 651, 10.1101/gad.186411.111

Ntziachristos, 2012, Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia., Nat Med, 18, 298, 10.1038/nm.2651

Zhang, 2012, The genetic basis of early T-cell precursor acute lymphoblastic leukaemia., Nature, 481, 157, 10.1038/nature10725