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

Nuclear receptor binding SET domain protein 2 (NSD2), also known as MMSET or WHSC1, is a histone methyltransferase that specifically catalyzes the dimethylation of lysine 36 on histone H3 (H3K36me2) (UniProt Q96L73). This epigenetic modification is generally associated with transcriptional activation and plays a critical role in chromatin structure and DNA damage response (PubMed 30104371). NSD2 is most notably linked to the t(4;14) chromosomal translocation found in approximately 15-20% of multiple myeloma patients, which leads to its massive overexpression and subsequent global increases in H3K36me2 levels (PubMed 21335234). Beyond myeloma, gain-of-function mutations like E1099K are prevalent in pediatric acute lymphoblastic leukemia, and its upregulation is observed in various solid tumors including prostate and breast cancers (PubMed 24633109). Therapeutic strategies currently focus on developing small-molecule inhibitors that target the catalytic SET domain or PROTACs to induce protein degradation, aiming to reverse the oncogenic epigenetic landscape (PubMed 34108476). Clinical-stage candidates like KTX-1001 are being evaluated for their ability to selectively inhibit NSD2 and reduce the proliferation of t(4;14)-positive cancer cells (NCT05651932).

Other names

MMSETWHSC1Multiple myeloma SET domain proteinWolf-Hirschhorn syndrome candidate 1TRX5Histone-lysine N-methyltransferase NSD2

Selective inhibition of the SET domain catalytic activity to reduce H3K36 dimethylation levels; targeted protein degradation via PROTACs