Mutant EZH2 Induces a Pre-malignant Lymphoma Niche by Reprogramming the Immune Response

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2020 May 13

PMID 32396861

Citations 67

Authors

Wendy Beguelin

Matt Teater

Cem Meydan

Kenneth B Hoehn

Jude M Phillip

Alexey A Soshnev

Leandro Venturutti

Martin A Rivas

Maria T Calvo-Fernandez

Johana Gutierrez

Jeannie M Camarillo

Katsuyoshi Takata

Karin Tarte

Neil L Kelleher

Christian Steidl

Christopher E Mason

Olivier Elemento

C David Allis

Steven H Kleinstein

Ari M Melnick

Affiliations

Soon will be listed here.

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.

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References

McCabe M, Ott H, Ganji G, Korenchuk S, Thompson C, Van Aller G . EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012; 492(7427):108-12. DOI: 10.1038/nature11606. View

Beguelin W, Teater M, Gearhart M, Fernandez M, Goldstein R, Cardenas M . EZH2 and BCL6 Cooperate to Assemble CBX8-BCOR Complex to Repress Bivalent Promoters, Mediate Germinal Center Formation and Lymphomagenesis. Cancer Cell. 2016; 30(2):197-213. PMC: 5000552. DOI: 10.1016/j.ccell.2016.07.006. View

Ortega-Molina A, Boss I, Canela A, Pan H, Jiang Y, Zhao C . The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development. Nat Med. 2015; 21(10):1199-208. PMC: 4676270. DOI: 10.1038/nm.3943. View

Schwammle V, Jensen O . A simple and fast method to determine the parameters for fuzzy c-means cluster analysis. Bioinformatics. 2010; 26(22):2841-8. DOI: 10.1093/bioinformatics/btq534. View

Souroullas G, Jeck W, Parker J, Simon J, Liu J, Paulk J . An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation. Nat Med. 2016; 22(6):632-40. PMC: 4899144. DOI: 10.1038/nm.4092. View

Chapuy B, Stewart C, Dunford A, Kim J, Kamburov A, Redd R . Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018; 24(5):679-690. PMC: 6613387. DOI: 10.1038/s41591-018-0016-8. View

Green M . Chromatin modifying gene mutations in follicular lymphoma. Blood. 2017; 131(6):595-604. PMC: 5805487. DOI: 10.1182/blood-2017-08-737361. View

Beguelin W, Popovic R, Teater M, Jiang Y, Bunting K, Rosen M . EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell. 2013; 23(5):677-92. PMC: 3681809. DOI: 10.1016/j.ccr.2013.04.011. View

Street K, Risso D, Fletcher R, Das D, Ngai J, Yosef N . Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genomics. 2018; 19(1):477. PMC: 6007078. DOI: 10.1186/s12864-018-4772-0. View

10.

Browning J, Dougas I, Ngam-Ek A, Bourdon P, Ehrenfels B, Miatkowski K . Characterization of surface lymphotoxin forms. Use of specific monoclonal antibodies and soluble receptors. J Immunol. 1995; 154(1):33-46. View

11.

Livet J, Weissman T, Kang H, Draft R, Lu J, Bennis R . Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature. 2007; 450(7166):56-62. DOI: 10.1038/nature06293. View

12.

Liao Y, Smyth G, Shi W . featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2013; 30(7):923-30. DOI: 10.1093/bioinformatics/btt656. View

13.

Mort R, Ford M, Sakaue-Sawano A, Lindstrom N, Casadio A, Douglas A . Fucci2a: a bicistronic cell cycle reporter that allows Cre mediated tissue specific expression in mice. Cell Cycle. 2014; 13(17):2681-96. PMC: 4613862. DOI: 10.4161/15384101.2015.945381. View

14.

Donaldson-Collier M, Sungalee S, Zufferey M, Tavernari D, Katanayeva N, Battistello E . EZH2 oncogenic mutations drive epigenetic, transcriptional, and structural changes within chromatin domains. Nat Genet. 2019; 51(3):517-528. DOI: 10.1038/s41588-018-0338-y. View

15.

Ferrari K, Scelfo A, Jammula S, Cuomo A, Barozzi I, Stutzer A . Polycomb-dependent H3K27me1 and H3K27me2 regulate active transcription and enhancer fidelity. Mol Cell. 2013; 53(1):49-62. DOI: 10.1016/j.molcel.2013.10.030. View

16.

Shlomchik M, Luo W, Weisel F . Linking signaling and selection in the germinal center. Immunol Rev. 2019; 288(1):49-63. PMC: 6422174. DOI: 10.1111/imr.12744. View

17.

Ersching J, Efeyan A, Mesin L, Jacobsen J, Pasqual G, Grabiner B . Germinal Center Selection and Affinity Maturation Require Dynamic Regulation of mTORC1 Kinase. Immunity. 2017; 46(6):1045-1058.e6. PMC: 5526448. DOI: 10.1016/j.immuni.2017.06.005. View

18.

Chao A, Hsieh T, Chazdon R, Colwell R, Gotelli N . Unveiling the species-rank abundance distribution by generalizing the Good-Turing sample coverage theory. Ecology. 2015; 96(5):1189-201. DOI: 10.1890/14-0550.1. View

19.

Hoehn K, Vander Heiden J, Zhou J, Lunter G, Pybus O, Kleinstein S . Repertoire-wide phylogenetic models of B cell molecular evolution reveal evolutionary signatures of aging and vaccination. Proc Natl Acad Sci U S A. 2019; 116(45):22664-22672. PMC: 6842591. DOI: 10.1073/pnas.1906020116. View

20.

Lee E, Chuang H, Kim J, Ideker T, Lee D . Inferring pathway activity toward precise disease classification. PLoS Comput Biol. 2008; 4(11):e1000217. PMC: 2563693. DOI: 10.1371/journal.pcbi.1000217. View