Overexpression and gain-of-function mutations in EZH2 are regarded as oncogenic drivers in lymphoma and other malignancies due to the silencing of tumor suppressors and differentiation genes.
Enhancer of zeste homolog 2 (EZH2) and Bcl-2 gene rearrangement or protein upregulation played pivotal roles in the carcinogenesis of various malignancies including lymphomas.
Enhancer of zeste homolog 2 (EZH2), an H3K27-specific histone methyltransferase, has been shown to be frequently overexpressed in various human cancers including lymphoma.
Furthermore, the overexpression of EZH2, in association with coexpression of tumorigenic signaling molecules, suggests an oncogenic role for this molecule in the development of Hodgkin lymphomas and related lymphomas.
2019; published online January 28, https://doi.org/10.1038/s41588-018-0338-y) examined the effects of mutant EZH2 on the 3D architecture of the lymphoma genome, highlighting the potential relevance of chromatin folding dynamics.
In this review, we present the rationale, key pre-clinical and early clinical findings of small molecule EZH2 inhibitors for use in lymphoma as well as future challenges and potential opportunities for combination therapies.
Here, we critically review the emerging role of EZH2 in malignancies, the development of small molecule inhibitors of EZH2, and their application in lymphoma.
Direct binding of MALAT1 to the PRC2 components (EZH2 and SUZ12) was observed in a T cell lymphoma cell line; however, no direct binding of MALAT1 with H3K27me3 and BMI1 (a PRC1 component) was observed.In T and NK cell lymphomas, MALAT1 was related to poor prognosis.
The antitumor efficacy of pharmacological EZH2 inhibition depends on SESTRIN1, indicating that mTORC1 control is a critical function of EZH2 in lymphoma.
We have previously shown that EZH2 inhibitors display an antiproliferative effect in multiple preclinical models of NHL, and that models bearing gain-of-function mutations in <i>EZH2</i> were consistently more sensitive to EZH2 inhibition than lymphomas with wild-type (WT) <i>EZH2</i> Here, we demonstrate that cell lines bearing <i>EZH2</i> mutations show a cytotoxic response, while cell lines with WT-<i>EZH2</i> show a cytostatic response and only tumor growth inhibition without regression in a xenograft model.
These results suggest that Ezh2(Y641F) induces lymphoma and melanoma through a vast reorganization of chromatin structure, inducing both repression and activation of polycomb-regulated loci.
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.
Several inhibitors of the PRC2 activity have shown efficacy in EZH2-mutated lymphomas and are currently in clinical development, although the molecular basis of inhibitor recognition remains unknown.
Insights into their biological mechanisms led to the development of therapies designed to target mutant IDH1 and IDH2, DOT1L in MLL-rearranged leukemias and EZH2 in several cancer types including lymphomas.
The reduction of CSC self-renewal via EZH2 inhibition offers a potentially attractive therapeutic approach to counter the aberrant activation found in lymphoma and leukemia.