EZH2 Cooperates with BCL6 to Drive Lymphomagenesis

Diffuse large B-cell lymphomas (DLBCL) arise from germinal center (GC) B cells, which exhibit upregulation of the histone methyltransferase EZH2 and often harbor activating mutations in EZH2, including EZH2^Y641. EZH2 shares many target genes with the transcriptional repressor BCL6, and loss of BCL6 or EZH2 function similarly to prevent GC formation and suppress lymphoma cell growth, prompting Béguelin and colleagues to determine if BCL6 and EZH2 cooperate in GC development. Knocking out Ezh2 or Bcl6 in the GC B cells of mice showed that EZH2 is required for BCL6-driven GC hyperplasia, and, conversely, BCL6 is required for EZH2^Y641-driven GC hyperplasia. EZH2 mediates H3K27 trimethylation (H3K27me3), and many bivalent promoters marked by H3K27me3 and H3K4me3 also exhibited BCL6 occupancy and recruitment of its corepressor BCOR, whereas monovalent promoters did not. Transcriptional repression of promoters marked by H3K27me3 is facilitated by polycomb repressive complex 1 (PRC1) complexes; however, the bivalent promoters lacked components of the canonical PRC1 complex, and instead BCOR formed an alternative noncanonical PRC1–BCOR complex that was required for EZH2^Y641-driven GC formation and GC hyperplasia. Both BCL6 and the EZH2-containing PRC2 complex were required for stable binding and repression of bivalent promoters by PRC1–BCOR. Mechanistically, CBX8, a chromodomain-containing component of PRC1–BCOR, recognized H3K27me3, allowing for PRC1–BCOR recruitment and repression of bivalent promoters. In vivo, EZH2^Y641 and constitutively expressed BCL6 cooperated to induce more rapid lymphomagenesis compared with either alone, and combined inhibition of EZH2 and BCL6 in DLBCL xenografts resulted in enhanced tumor inhibition and was well tolerated in mice. These findings elucidate a mechanism by which EZH2 and BCL6 cooperate to repress bivalent promoters in GC B cells, and provide a rationale for combined treatment with EZH2 and BCL6 inhibitors in patients with DLBCL.

Béguelin W, Teater M, Gearhart MD, Calvo Fernández MT, Goldstein RL, Cárdenas MG, et al. EZH2 and BCL6 cooperate to assemble CBX8-BCOR complex to repress bivalent promoters, mediate germinal center formation and lymphomagenesis. Cancer Cell 2016;30:197–213.