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

Wendy Béguelin*, Matt Teater, Cem Meydan, Kenneth B. Hoehn, Jude M. Phillip, Alexey A. Soshnev, Leandro Venturutti, Martín A. Rivas, María T. Calvo-Fernández, 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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)655-673.e11
JournalCancer Cell
Issue number5
StatePublished - May 11 2020


  • EZH2
  • epigenetic dysregulation
  • follicular lymphoma
  • germinal center
  • immune microenvironment

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research


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