Nuclear receptor-binding SET domain-containing protein 2 (NSD2)

NSD2 (also known as MMSET or WHSC1) is a multidomain histone methyltransferase highly expressed due to chromosomal translocations in approximately 15–20% of multiple myeloma cases, particularly in patients with the t(4;14) translocation[2][3][4][5][6]. It catalyzes mono- and di-methylation of lysine 36 on histone H3 (H3K36me1/2), regulating gene expression by antagonizing Polycomb Repressive Complex 2 and altering chromatin dynamics[3][4]. Overexpression leads to widespread epigenetic dysregulation, derepression of normally silenced genes, and tumorigenesis[3][5]. NSD2 mutations or deletions are also implicated in Wolf-Hirschhorn syndrome, a developmental disorder[6][7]. In multiple myeloma, NSD2 overexpression is linked to aggressive disease, supporting its role as a therapeutic target; however, to date, no specific NSD2 inhibitors have been clinically approved[2][5].

Other names

MMSETWolf-Hirschhorn syndrome candidate 1 (WHSC1)TRX5REIIBPHistone-lysine N-methyltransferase NSD2

Inhibition of methyltransferase activity (main target: methylation of H3K36), epigenetic transcriptional repression or activation, chromatin modification