title: Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis.
abstract: Mutations in the gene encoding the KMT2D (or MLL2) methyltransferase are highly recurrent and occur early during tumorigenesis in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). However, the functional consequences of these mutations and their role in lymphomagenesis are unknown. Here we show that FL- and DLBCL-associated KMT2D mutations impair KMT2D enzymatic activity, leading to diminished global H3K4 methylation in germinal-center (GC) B cells and DLBCL cells. Conditional deletion of Kmt2d early during B cell development, but not after initiation of the GC reaction, results in an increase in GC B cells and enhances B cell proliferation in mice. Moreover, genetic ablation of Kmt2d in mice overexpressing Bcl2 increases the incidence of GC-derived lymphomas resembling human tumors. These findings suggest that KMT2D acts as a tumor suppressor gene whose early loss facilitates lymphomagenesis by remodeling the epigenetic landscape of the cancer precursor cells. Eradication of KMT2D-deficient cells may thus represent a rational therapeutic approach for targeting early tumorigenic events.
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Jiyuan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.|Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: David
authors.initials: D
authors.lastname: Dominguez-Sola
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Shafinaz
authors.initials: S
authors.lastname: Hussein
authors.affiliation: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Antony B
authors.initials: AB
authors.lastname: Holmes
authors.affiliation: Department of Systems Biology, Columbia University, New York, New York, USA.
authors.forename: Mukesh
authors.initials: M
authors.lastname: Bansal
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Sofija
authors.initials: S
authors.lastname: Vlasevska
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Tongwei
authors.initials: T
authors.lastname: Mo
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Tang
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.|Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.
authors.forename: Katia
authors.initials: K
authors.lastname: Basso
authors.affiliation: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Ge
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.|Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.|Department of Genetics &Development, Columbia University, New York, New York, USA.|Department of Microbiology &Immunology, Columbia University, New York, New York, USA.|Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dalla-Favera
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.|Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.|Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Pasqualucci
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology; D049109:Cell Proliferation; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D018858:Germinal Center / Q000166:cytology*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000209:etiology / Q000235:genetics*; D051379:Mice; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; D009363:Neoplasm Proteins