EZH inhibitors in lymphoma therapy

Enhancer of zeste homolog (EZH), a subunit of polycomb repressive complex 2 (PRC2), suppresses gene expression by methylation of H3K27. EZH is closely associated with B-cell development and pathogenesis of certain malignant lymphomas. In follicular lymphoma (FL), gain-of-function mutation and upregulation of EZH2 are observed in approximately 30% and 15% of cases, respectively. Moreover, one-third of diffuse large B-cell lymphomas carry an EZH2 mutation, mostly co-existing with translocation involving Bcl-2. Genome-wide trimethylation of H3K27 is a unique characteristic induced by upregulation of both EZH2 and EZH1, and is responsible for more than half of the gene suppression that occurs in adult T-cell leukemia/lymphoma (ATL). Inhibition of EZH can reduce H3K27 methylation and subsequently restore epigenetically suppressed genes. Currently, an EZH2 inhibitor and dual EZH1/2 inhibitor have been clinically used to treat relapsed/refractory FL and ATL, respectively. EZH-targeted treatment for lymphoma has only just begun, and further development of these drugs for various other malignancies, both alone and in combination with other therapeutics, is ongoing.