NSD2
Overview
NSD2 (Nuclear Receptor Binding SET Domain Protein 2; also WHSC1/MMSET) encodes a histone H3K36 methyltransferase. Overexpression driven by the t(4;14) translocation is a well-established driver in plasma-cell myeloma (PCM). In mantle cell lymphoma (MCL), recurrent somatic missense mutations in NSD2 were first described by TCGA analyses; these mutations phenocopy the t(4;14) transcriptional program, implicating NSD2 gain-of-function as an epigenetic driver beyond PCM.
Alterations observed in the corpus
- Recurrent missense mutations p.E1099K and p.T1150A (in conserved SET-domain–proximal exons 18/19) in 13/130 (10%) MCL; first description of NSD2/WHSC1 somatic mutation in lymphoma; nearly all in SOX11-positive tumors; likely late/subclonal event in some cases PMID:24145436
- NSD2-mutated MCL phenocopies t(4;14) plasma-cell myeloma transcriptionally: GSEA shows overexpression of NSD2 gain-of-function gene signatures and proliferation/cell-cycle signatures PMID:24145436
Cancer types (linked)
- MCL — recurrent missense mutations in 10% of MCL; SOX11-positive tumors preferentially affected; late/subclonal in paired evolution analysis PMID:24145436
Co-occurrence and mutual exclusivity
- Enriched in SOX11-positive / IGHV-unmutated MCL; co-occurs with ATM, KMT2D mutations in chromatin-modifier-enriched MCL subset PMID:24145436
- NSD2 mutations appear as likely late events: observed in only one of two paired subclones in sequential-sample analysis PMID:24145436
Therapeutic relevance
- NSD2 inhibitors are under investigation in PCM; potential relevance to MCL given phenocopy of t(4;14) transcriptional program; no clinical data in MCL currently in corpus.
Open questions
- Whether NSD2 missense mutations in MCL confer gain-of-function H3K36 methyltransferase activity equivalent to the t(4;14) NSD2 overexpression in PCM remains to be established.
- Prognostic impact of NSD2 mutation in MCL independent of SOX11 status is not yet defined.
Sources
This page was processed by crosslinker on 2026-05-09.