Ezh2-mutant germinal center B cells depended on follicular dendritic cells rather than Tfh cells.

  • Major Finding:Ezh2-mutant germinal center B cells depended on follicular dendritic cells rather than Tfh cells.

  • Mechanism: Mutant EZH2 caused methylation-based repression of genes involved in Tfh signaling to centrocytes.

  • Impact: This shows how follicular lymphomas arise from germinal center B cells by altering the immune niche.

Follicular lymphomas are slow-growing tumors that arise, perplexingly, from highly proliferative germinal center (GC) B cells. Gain-of-function mutations in the histone methyltransferase EZH2 frequently occur in follicular lymphoma, spurring Béguelin and colleagues to investigate the role of a common EZH2 gain-of-function mutation (Y641F) in follicular lymphoma. In mice, Ezh2Y641F-mutant GC B cells exhibited a selective advantage over Ezh2–wild-type GC B cells, and Ezh2Y641F mutation caused enrichment of centrocytes (which contribute to the GC light zone) in splenic GCs. This enrichment was not caused by reduced differentiation of centrocytes into plasma or memory cells but rather by increased proliferation and reduced apoptosis of centrocytes along with failure of light-zone centrocytes to undergo MYC-mediated reentry into the dark zone. Mechanistically, Ezh2Y641F-mutant GC B cells had increased histone 3 lysine residue 27 trimethylation (H3K27me3, a mark associated with transcriptional repression), particularly around genes that are normally repressed by EZH2 in GC B cells, but also at promoters of some nearby genes. The major impact of the observed increase in H3K27me3 was aberrant transcriptional repression of genes that are typically dynamically regulated during the GC reaction, including genes involved in signaling by T follicular helper (Tfh) cells to centrocytes. Ezh2Y641F-mutant GC B cells had reduced dependence on Tfh cells for survival and expansion in the light zone. Instead of depending on Tfh cells, Ezh2Y641F-mutant GC B cells depended on follicular dendritic cells, which are abundant in follicular lymphomas. In summary, this work provides a mechanistic basis for the way EZH2 mutation reprograms the premalignant immune niche to foster the development of follicular lymphoma from GC B cells.

Béguelin W, Teater M, Meydan C, Hoehn KB, Phillip JM, Soshnev AA, et al. Mutant EZH2 induces a pre-malignant lymphoma niche by reprogramming the immune response. Cancer Cell 2020;37:655–73.E1.

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