9y61
Cryo-EM structure of ternary complex NSD2-PWWP1:CRBN:DDB1 in complex with NSD2-LDD, an LDD degrader
Structural highlights
DiseaseNSD2_HUMAN Wolf-Hirschhorn syndrome. A chromosomal aberration involving WHSC1 is a cause of multiple myeloma tumors. Translocation t(4;14)(p16.3;q32.3) with IgH. WHSC1 is located in the Wolf-Hirschhorn syndrome (WHS) critical region. WHS results from by sub-telomeric deletions in the short arm of chromosome 4. WHSC1 is deleted in every case, however deletion of linked genes contributes to both the severity of the core characteristics and the presence of the additional syndromic problems. FunctionNSD2_HUMAN Histone methyltransferase with histone H3 'Lys-27' (H3K27me) methyltransferase activity. Isoform 2 may act as a transcription regulator that binds DNA and suppresses IL5 transcription through HDAC recruitment.[1] [2] [3] Publication Abstract from PubMedThe t(4;14) chromosomal translocation drives overexpression of the histone methyltransferase NSD2 and defines a high-risk segment of multiple myeloma (MM) patients. Herein, we report the discovery of NSD2-LDD, a cereblon-recruiting and PWWP1-mediated ligand directed degrader (LDD) that selectively and potently eliminates full length and PWWP1 domain containing NSD2 protein isoforms. NSD2-LDD treatment induces global loss of H3K36me2 leading to promoter-proximal spreading of H3K27me3 and re-wiring of cis-regulatory interactions that reverse t(4;14) transcriptional programs. These effects suppress MM disease-associated phenotypes including stromal adhesion, three-dimensional colony growth and paracrine signaling. By integrating patient single cell profiles with model 3D epigenomic and spatial transcriptomics, we delineate t(4;14) disease state together with the tumor-intrinsic reprogramming and resultant remodeling of the bone marrow microenvironment upon NSD2 degradation. In cell line derived xenografts and genetically engineered mouse models of t(4;14), NSD2-LDD extends median survival accompanied by tumoral H3K36me2 loss and niche re-modelling. Although the NSD2-LDD response is restricted to PWWP1-containining models, collectively this work validates NSD2 as a tractable dependency and supports clinical development of NSD2 degradation as a novel, targeted therapeutic strategy in high-risk MM. NSD2 Degradation Remediates the Oncogenic Cistrome in t(4;14) Multiple Myeloma.,Hu B, Edwards J, Modi H, Gamez J, Echeagaray OE, Hess K, Ren Y, Anderson D, Larrayoz M, Zhu J, Johnson SA, Deb G, Jankeel D, Janardhanan P, Leisten J, Peng S, Christoforou A, Stong N, Fontanillo C, Bjorklund CC, Hagner PR, Gandhi AK, Martinez-Climent JA, Narla RK, Lopez-Girona A, Rolfe M, Bence N, Mortensen DS, Groocock L Blood. 2026 Jun 29:blood.2025031998. doi: 10.1182/blood.2025031998. PMID:42371798[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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