Enhancer of zeste homolog 2 Y641N mutant (EZH2 Y641N)

Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), an essential epigenetic regulator that mediates gene silencing through the trimethylation of Lysine 27 on Histone H3 (H3K27me3) [3, 11]. The Y641N mutation is a recurrent somatic gain-of-function alteration found in approximately 22% of germinal center B-cell-like diffuse large B-cell lymphomas (GCB-DLBCL) and 7-18% of follicular lymphomas [1, 5]. While wild-type EZH2 primarily catalyzes the monomethylation of H3K27, the Y641N mutant possesses a shifted substrate preference that highly favors the conversion of dimethylated H3K27 to the trimethylated state [6, 7]. This results in global H3K27me3 hyper-trimethylation and the constitutive repression of genes involved in B-cell differentiation and tumor suppression [8, 14]. Therapeutic targeting of the EZH2 Y641N mutant involves small-molecule inhibitors like Tazemetostat, which act as S-adenosyl-L-methionine (SAM) competitors to block the enzyme's methyltransferase activity and restore normal gene expression patterns [9, 16]. Clinical challenges include the development of acquired resistance through secondary mutations in the EZH2 SET domain and potential safety concerns such as myelosuppression and the risk of secondary malignancies [13, 16].

Other names

KMT6 Y641NENX-1 Y641NLysine N-methyltransferase 6 Y641NEnhancer of zeste 2 polycomb repressive complex 2 subunit Y641N

Small molecule inhibition of the EZH2 methyltransferase activity, typically through competition with the methyl donor S-adenosyl-L-methionine (SAM), to reduce H3K27 trimethylation levels.