EZH2, as transcriptional repressor, is mutated in high frequency in Chinese and Western patients with follicular lymphoma and may represent a rational target for GC-derived lymphomas..
New therapeutic approaches targeting aberrant H3K27 methylation include small molecules that block the action of mutant EZH2 in germinal center-derived lymphoma.
These genomic data suggest that targeting the EZH2 MT activity is a valid therapeutic strategy for the treatment of lymphoma patients with EZH2 mutations.
Therefore, our study uncovers an oncogenic role of EZH2 independent of its methyltransferase activity in NKTL and suggests that targeting EZH2 may have therapeutic usefulness in this lymphoma.
Combined inhibition of HDAC3 and EZH2 cooperatively disrupted the MYC-EZH2-miR-29 axis, resulting in restoration of miR-29 expression, downregulation of miR-29-targeted genes, and lymphoma growth suppression in vitro and in vivo.
EZH2 mediated transcriptional repression through its methyltransferase activity at the chromatin level has certain influence on lymphoma, and there might exist a therapeutic window for the development of new agents and identification of novel diagnostic markers based on EZH2.
Mutation of EZH2 Y641 is described in lymphoma and results in enhanced activity, whereas inactivating mutations are seen in poor prognosis myeloid neoplasms.
This represents the first example of a disease-associated gain-of-function mutation in a histone methyltransferase, whereby somatic EZH2 Y641 mutations in lymphoma act dominantly to increase, rather than decrease, histone methylation.
EZH2 mutations were frequently associated with the presence of BCL2 rearrangement (BCL2-R) in both the FL (28% of BCL-R cases versus 0% of BCL2-WT cases, p<0.05) and GCB-DLBCL groups (33% of BCL2-R cases versus 4% of BCL2-WT cases, p<0.04), and across all lymphoma types excluding BL (27% of BCL2-R cases versus 3% of BCL2-WT cases, p<0.003).