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

Wendy Beguelin 1, * Matt Teater 1 Cem Meydan 1 Kenneth B. Hoehn 2 Jude M. Phillip 1 Alexey A. Soshnev 3 Leandro Venturutti 1 Martin A. Rivas 1 Maria T. Calvo-Fernandez 1 Johana Gutierrez 1 Jeannie M. Camarillo 4 Katsuyoshi Takata 5 Karin Tarte 6 Neil L. Kelleher 4 Christian Steidl 5 Christopher E. Mason 1, 7 Olivier Elemento 1 C. David Allis 3 Steven H. Kleinstein 2 Ari M. Melnick 1, *
* Corresponding author
1 Cornell University [New York]
2 Yale University School of Medicine
3 Rockefeller University [New York]
4 Northwestern University [Evanston]
5 British Columbia
6 MICMAC - Microenvironment, Cell Differentiation, Immunology and Cancer
7 Weill Medical College of Cornell University [New York]
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.
Keywords : germinal center immune microenvironment EZH2 epigenetic dysregulation follicular lymphoma
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https://hal-univ-rennes1.archives-ouvertes.fr/hal-02797079
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Submitted on : Friday, June 5, 2020 - 2:27:34 PM
Last modification on : Tuesday, January 4, 2022 - 10:12:02 AM

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UNIV-RENNES1 | U917 | BIOSIT | UR1-UFR-SVE | MICMAC | UNIV-RENNES | UR1-BIO-SA

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Wendy Beguelin, Matt Teater, Cem Meydan, Kenneth B. Hoehn, Jude M. Phillip, et al.. Mutant EZH2 Induces a Pre-malignant Lymphoma Niche by Reprogramming the Immune Response. Cancer Cell, Elsevier, 2020, 37 (5), pp.655-+. ⟨10.1016/j.ccell.2020.04.004⟩. ⟨hal-02797079⟩

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