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

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 in mice. 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 in B-cells, and in human B-cell lymphomas. Conditional expression of mutant EZH2 in mice induces GC hyperplasia and accelerated lymphomagenesis in cooperation with BCL2. GCB-type DLBCLs are mostly addicted to EZH2, regardless of mutation status, but not the more differentiated ABC-type DLBCLs, thus clarifying the therapeutic scope of EZH2 targeting.

The SWI/SNF chromatin remodeling complex regulates germinal center formation by repressing Blimp-1 expression

“…Previous studies have shown that Ezh2 is required for GC formation and the SWI/SNF complex synergistically regulates several genes together with the Ezh2-PRC2 complex (36)(37)(38)(39). MTA3, a subunit of the NuRD complex, is also known to interact with Bcl-6 and to inhibit Blimp-1 expression (40).…”

Chromatin proteins and modifications as drug targets

“…The biology is therefore complex, and depending on the tissue and the underlying genetic landscape of the cell, the chromatin--associated protein could act as an oncogene in one setting but be a tumour suppressor in other circumstances. This is for instance illustrated by EZH2, in which gain--of--function mutations promote lymphoid transformation 16,33,37,79 , and loss--of--function mutations promote MDS and T--ALL 36,80--83 .…”

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

“…83 EZH2 has been described as an essential regulator for B cell activation and is involved in germinal center-derived neoplasms. 84 In myeloid neoplasia, EZH2 is most often affected by mutations leading to direct abrogation of histone methyltransferase activity, suggesting that EZH2 acts as a tumor suppressor for myeloid malignancies. 79 There is evidence for both increased and decreased activity of enzymes controlling H3K27 methylation in other cancers, 76,85 supporting the idea that a precise balance of this methylation is critical for normal cell growth and for a context-dependent role of polycomb proteins in oncogenesis.…”