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

TitleMutant EZH2 Induces a Pre-malignant Lymphoma Niche by Reprogramming the Immune Response.
Publication TypeJournal Article
Year of Publication2020
AuthorsBéguelin 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, C Allis D, Kleinstein SH, Melnick AM
JournalCancer Cell
Date Published2020 May 11

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.

Alternate JournalCancer Cell
PubMed ID32396861
PubMed Central IDPMC7298875
Grant ListR01 CA198089 / CA / NCI NIH HHS / United States
R35 CA220499 / CA / NCI NIH HHS / United States
P41 GM108569 / GM / NIGMS NIH HHS / United States
R01 AI104739 / AI / NIAID NIH HHS / United States
P30 CA060553 / CA / NCI NIH HHS / United States