EZH2 Is Required for Germinal Center Formation and Somatic EZH2 Mutations Promote Lymphoid Transformation

Wendy Béguelin, Relja Popovic, Matt Teater, Yanwen Jiang, Karen L. Bunting, Monica Rosen, Hao Shen, Shao Ning Yang, Ling Wang, Teresa Ezponda, Eva Martinez-Garcia, Haikuo Zhang, Yupeng Zheng, Sharad K. Verma, Michael T. McCabe, Heidi M. Ott, Glenn S. VanAller, Ryan G. Kruger, Yan Liu, Charles F. McHughDavid W. Scott, Young Rock Chung, Neil Kelleher, Rita Shaknovich, Caretha L. Creasy, Randy D. Gascoyne, Kwok Kin Wong, Leandro Cerchietti, Ross L. Levine, Omar Abdel-Wahab, Jonathan D. Licht, Olivier Elemento, Ari M. Melnick

Research output: Contribution to journalArticle

Abstract

The EZH2 histone methyltransferase is highly expressed in germinal center (GC) B cells and targeted by somatic mutations in B cell lymphomas. Here, we find that EZH2 deletion or pharmacologic inhibition suppresses GC formation and functions. EZH2 represses proliferation checkpoint genes and helps establish bivalent chromatin domains at key regulatory loci to transiently suppress GC B cell differentiation. Somatic mutations reinforce these physiological effects through enhanced silencing of EZH2 targets. Conditional expression of mutant EZH2 in mice induces GC hyperplasia and accelerated lymphomagenesis in cooperation with BCL2. GC B cell (GCB)-type diffuse large B cell lymphomas (DLBCLs) are mostly addicted to EZH2 but not the more differentiated activated B cell (ABC)-type DLBCLs, thus clarifying the therapeutic scope of EZH2 targeting.

Original languageEnglish (US)
Pages (from-to)677-692
Number of pages16
JournalCancer cell
Volume23
Issue number5
DOIs
StatePublished - May 13 2013
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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  • Cite this

    Béguelin, W., Popovic, R., Teater, M., Jiang, Y., Bunting, K. L., Rosen, M., Shen, H., Yang, S. N., Wang, L., Ezponda, T., Martinez-Garcia, E., Zhang, H., Zheng, Y., Verma, S. K., McCabe, M. T., Ott, H. M., VanAller, G. S., Kruger, R. G., Liu, Y., ... Melnick, A. M. (2013). EZH2 Is Required for Germinal Center Formation and Somatic EZH2 Mutations Promote Lymphoid Transformation. Cancer cell, 23(5), 677-692. https://doi.org/10.1016/j.ccr.2013.04.011