Cancer Cell
Volume 23, Issue 5, 13 May 2013, Pages 677-692
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Article
EZH2 Is Required for Germinal Center Formation and Somatic EZH2 Mutations Promote Lymphoid Transformation

https://doi.org/10.1016/j.ccr.2013.04.011Get rights and content
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Highlights

  • EZH2 is required for germinal center formation and immunoglobulin affinity maturation

  • Conditional expression of an EZH2 mutant lymphoma allele drives GC hyperplasia in vivo

  • Mutant EZH2 functions in part through aberrant repression of GC-specific bivalent promoters

  • EZH2 cooperates with BCL2 to initiate and maintain diffuse large B cell lymphomas

Summary

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.

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These authors contributed equally to this work