EZH2 and BCL6 Cooperate to Assemble CBX8-BCOR Complex to Repress Bivalent Promoters, Mediate Germinal Center Formation and Lymphomagenesis

Abstract

SUMMARY The EZH2 histone methyltransferase mediates the humoral immune response and drives lymphomagenesis through formation of bivalent chromatin domains at critical germinal center (GC) B cell promoters. Herein we show that the actions of EZH2 in driving GC formation and lymphoma precursor lesions require site-specific binding by the BCL6 transcriptional repressor and the presence of a non-canonical PRC1-BCOR-CBX8 complex. The chromodomain protein CBX8 is induced in GC B cells, binds to H3K27me3 at bivalent promoters, and is required for stable association of the complex and the resulting histone modifications. Moreover, oncogenic BCL6 and EZH2 cooperate to accelerate diffuse large B cell lymphoma (DLBCL) development and combinatorial targeting of these repressors results in enhanced anti-lymphoma activity in DLBCLs.

EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL

“…It was recently discovered that treatment of normal B-cells or DLBCL cell lines with small-molecule inhibitors of EZH2 can induce several hallmarks of B-cell maturation (immunoglobulin and PRDM1 induction; refs. 7,10,22) and that B-cell maturation in the lymph node is controlled by the transcriptional repressive effects of BCL6 and EZH2 (23). These reports are consistent with many studies that have explored the effects of EZH2 inhibitors in cell lines derived from B-cell lymphomas.…”

Impairment of both IRE1 expression and XBP1 activation is a hallmark of GCB DLBCL and contributes to tumor growth

“…This subtype is characterized by overexpression of BCL6 12 , a transcriptional suppressor that down-regulates genes involved in plasma cell differentiation 13,14 and contributes to disease onset by blocking B cells in the germinal center stage 15,16 . Histone methyl-transferase EZH2 is another frequently mutated 17,18 transcriptional regulator that co-operates with aberrant BCL6 activity to promote GCB DLBCL pathology 19,20 . EZH2, the catalytic subunit of the Polycomb Repressor Complex 2, mediates Histone 3 Lysine 27 methylation (H3K27me3) leading to chromatin condensation and repression of its target genes 21,22 .…”

Rituximab-Based Therapy in Newly Diagnosed Diffuse Large B-Cell Lymphoma Patients: Individualized Risk-Adapted Therapy Approach Using Molecular Subtypes

“…Chronic active B-cell receptor (BCR) signaling, constitutive myeloid differentiation primary response gene 88 (MYD88) signaling, and subsequent antiapoptotic nuclear factor-kappa B (NF-kappaB) pathway, phosphatidylinositol-3-kinase/serine-threonine kinase (PI3K/Akt/mTOR) pathway, and interferon pathway activation are characteristics of the ABC DLBCL [7,24,32]. On the other hand, BCL6 and EZH2 together are extensively studied in the GCB subtype of DLBCL [33].…”

“…BCL6 and EZH2 together accelerate lymphomagenesis in the GCB subtype of DLBCL [33]. With encouraging pre-clinical results, EZH2 inhibitors are currently being investigated in phase 1 and 2 clinical trials [70][71][72][73] and have the potential for greater tumor specificity and lower generalized toxicity.…”

“…The significantly better efficacy of R-CHOP versus CHOP (the 10-year progressionR-Based Therapy in Newly Diagnosed DLBCL J Hematol. 2017;6(2-3): [33][34][35][36][37][38][39][40][41][42][43] ern Cooperative Oncology Group (ECOG) 4494/Cancer and Leukemia Group B (CALGB) 9793 (E4494/C9793) phase 3 trial conducted in DLBCL patients ≥ 60 years old showed that rituximab as administered during induction or maintenance phases in addition to CHOP significantly improved FFS [16]. The MabThera International Trial (MInT) Group study was the first to demonstrate improved efficacy and comparable tolerability of R-CHOP-like treatment compared with CHOPlike chemotherapy in young patients (aged 18 -60 years) with good-prognosis DLBCL [17,18].…”