title: The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development.
abstract: The gene encoding the lysine-specific histone methyltransferase KMT2D has emerged as one of the most frequently mutated genes in follicular lymphoma and diffuse large B cell lymphoma; however, the biological consequences of KMT2D mutations on lymphoma development are not known. Here we show that KMT2D functions as a bona fide tumor suppressor and that its genetic ablation in B cells promotes lymphoma development in mice. KMT2D deficiency also delays germinal center involution and impedes B cell differentiation and class switch recombination. Integrative genomic analyses indicate that KMT2D affects methylation of lysine 4 on histone H3 (H3K4) and expression of a set of genes, including those in the CD40, JAK-STAT, Toll-like receptor and B cell receptor signaling pathways. Notably, other KMT2D target genes include frequently mutated tumor suppressor genes such as TNFAIP3, SOCS3 and TNFRSF14. Therefore, KMT2D mutations may promote malignant outgrowth by perturbing the expression of tumor suppressor genes that control B cell-activating pathways.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Ortega-Molina
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA.|Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Isaac W
authors.initials: IW
authors.lastname: Boss
authors.affiliation: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Canela
authors.affiliation: Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Heng
authors.initials: H
authors.lastname: Pan
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA.|Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.
authors.forename: Chunying
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.
authors.forename: Man
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois, USA.
authors.forename: Deqing
authors.initials: D
authors.lastname: Hu
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA.|Area de Oncología, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain.
authors.forename: Xabier
authors.initials: X
authors.lastname: Agirre
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA.|Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Itamar
authors.initials: I
authors.lastname: Niesvizky
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: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Hua-Tang
authors.initials: HT
authors.lastname: Chen
authors.affiliation: Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ennishi
authors.affiliation: Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: David W
authors.initials: DW
authors.lastname: Scott
authors.affiliation: Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Anja
authors.initials: A
authors.lastname: Mottok
authors.affiliation: Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Hother
authors.affiliation: Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Shichong
authors.initials: S
authors.lastname: Liu
authors.affiliation: Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Xing-Jun
authors.initials: XJ
authors.lastname: Cao
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Wayne
authors.initials: W
authors.lastname: Tam
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Shaknovich
authors.affiliation: Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Garcia
authors.affiliation: Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
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: Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Shilatifard
authors.affiliation: Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Andre
authors.initials: A
authors.lastname: Nussenzweig
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, USA.|Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Ari M
authors.initials: AM
authors.lastname: Melnick
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.
authors.forename: Hans-Guido
authors.initials: HG
authors.lastname: Wendel
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000209:etiology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; D009363:Neoplasm Proteins