Degradation of PRC2 with UNC6852 blocks the histone methyltransferase activity of EZH2, decreasing H3K27me3 levels in HeLa cells and diffuse large B cell lymphoma (DLBCL) cells containing EZH2 gain-of-function mutations.
In this study, we treated Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) cell lines with 3-deazaneplanocin-A (DZNep), an indirect EZH2 inhibitor which possesses anticancer properties both in-vitro and in-vivo.
Germinal center-like DLBCL is enriched for activating EZH2 mutations, and encouraging activity has been observed for the EZH2 inhibitor tazemetostat, which now has a fast-track US Food and Drug Administration designation.
EZH2 inhibitors reversed the upregulation of trimethylation of H3K27, and synergistically inhibited diffuse large B-cell lymphoma and other solid tumors growth in vitro and in vivo.
Univariate analyses revealed that EZH2/Bcl-2 coexpression correlated to worse objective response rate (ORR), shorter OS and PFS in DLBCL patients treated with RCHOP while multivariate analysis indicated that only elevated LDH level (<i>P</i>=0.001) and presence of B symtom (<i>P</i>=0.008) rather than EZH2/Bcl-2 coexpression were associated with worse OS.
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.
We investigated the potential signaling molecules that regulate EZH2 overexpression in aggressive B-cell lymphomas and found that 80% of cases of EZH2-positive diffuse large B-cell lymphoma show high p-ERK1/2 expression (average ~57% tumor cell positivity).
Prioritized alterations in epigenetic modulators were common and included gain-of-function EZH2 and loss-of-function ARID1A mutations (14% of diffuse large B-cell lymphomas and 22% of follicular lymphomas contained alterations in each of these two genes).
HDAC1,2 inhibition impairs EZH2- and BBAP-mediated DNA repair to overcome chemoresistance in EZH2 gain-of-function mutant diffuse large B-cell lymphoma.
Here, we discuss the function of histone acetyltransferases (CREBBP, EP300), histone methyltransferases (KDM2C/D, EZH2) and regulators of higher order chromatin structure (HIST1H1C/D/E, ARID1A and SMARCA4) that have been reported to be mutated in ⩾5% of DLBCL, FL or BL.
Recurrent somatic heterozygous gain-of-function mutations of EZH2 have been identified in DLBCL, most notably affecting tyrosine 641 (Y641), inducing hyper-trimethylation of H3K27 (H3K27me3).
In particular, recurrent gain-of-function mutations targeting EZH2 Y641 occur most frequently in follicular lymphoma and aggressive diffuse large B-cell lymphoma and are associated with H3K27me3 hyperactivation, which contributes to lymphoma pathogenesis.
Activating mutations of genes involved in the BCR and NF-κB pathways (CD79A, CD79B, MYD88, and CARD11) or in epigenetic regulation (EZH2) have been recently reported, preferentially in one of the two DLBCL subtypes.
Mutations in EZH2 (Y646) and CD79B (Y196) were detected in 13.2% and 8% of the samples, respectively, almost exclusively in follicular lymphomas and diffuse large B-cell lymphomas.