1. Mutant EZH2 Induces a Pre-malignant Lymphoma Niche by Reprogramming the Immune Response.
- Author
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Béguelin W, Teater M, Meydan C, Hoehn KB, Phillip JM, Soshnev AA, Venturutti L, Rivas MA, Calvo-Fernández MT, Gutierrez J, Camarillo JM, Takata K, Tarte K, Kelleher NL, Steidl C, Mason CE, Elemento O, Allis CD, Kleinstein SH, and Melnick AM
- Subjects
- Animals, B-Lymphocytes metabolism, B-Lymphocytes pathology, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic pathology, Dendritic Cells immunology, Dendritic Cells metabolism, Dendritic Cells pathology, Female, Germinal Center immunology, Germinal Center metabolism, Germinal Center pathology, Humans, Lymphoma, B-Cell genetics, Lymphoma, B-Cell pathology, Lymphoma, Follicular genetics, Lymphoma, Follicular pathology, Mice, Mice, Inbred C57BL, B-Lymphocytes immunology, Cell Transformation, Neoplastic immunology, Cellular Reprogramming, Enhancer of Zeste Homolog 2 Protein genetics, Lymphoma, B-Cell immunology, Lymphoma, Follicular immunology, Mutation
- Abstract
Follicular lymphomas (FLs) are slow-growing, indolent tumors containing extensive follicular dendritic cell (FDC) networks and recurrent EZH2 gain-of-function mutations. Paradoxically, FLs originate from highly proliferative germinal center (GC) B cells with proliferation strictly dependent on interactions with T follicular helper cells. Herein, we show that EZH2 mutations initiate FL by attenuating GC B cell requirement for T cell help and driving slow expansion of GC centrocytes that become enmeshed with and dependent on FDCs. By impairing T cell help, mutant EZH2 prevents induction of proliferative MYC programs. Thus, EZH2 mutation fosters malignant transformation by epigenetically reprograming B cells to form an aberrant immunological niche that reflects characteristic features of human FLs, explaining how indolent tumors arise from GC B cells., Competing Interests: Declaration of Interests A.M.M. is consulting for Epizyme and Constellation Pharmaceuticals, and receives research funding from Janssen Pharmaceuticals; S.H.K. is consulting for Northrop Grumman; C.E.M. is a co-founder and equity stake holder for Onegevity Health and Biotia, Inc.; C.S. has performed consultancy for Seattle Genetics, Curis Inc., Roche, AbbVie, Juno Therapeutics, and Bayer, and has received research funding from Bristol-Myers Squibb and Trillium Therapeutics, Inc. There are no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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