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TitleNSD2 Degradation Remediates the Oncogenic Cistrome in t(4;14) Multiple Myeloma.
Journal, issue, pagesBlood, Year 2026
Publish dateJun 29, 2026
AuthorsBo Hu / Jacob Edwards / Hardik Modi / Jim Gamez / Oscar Enrique Echeagaray / Kyle Hess / Yue Ren / Diana Anderson / Marta Larrayoz / Jinyi Zhu / Scott Arne Johnson / Gauri Deb / Diana Jankeel / Preethi Janardhanan / Jim Leisten / Sophie Peng / Andy Christoforou / Nicholas Stong / Celia Fontanillo / Chad C Bjorklund / Patrick Ryan Hagner / Anita Krithivas Gandhi / Jose A Martínez-Climent / Rama Krishna Narla / Antonia Lopez-Girona / Mark Rolfe / Neil Bence / Deborah S Mortensen / Lynda Groocock /
PubMed AbstractThe 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 ...The 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.
External linksBlood / PubMed:42371798
MethodsEM (single particle) / X-ray diffraction
Resolution2.023 - 3.1 Å
Structure data

72526

9y61

EMDB-72526, PDB-9y61:
Cryo-EM structure of ternary complex NSD2-PWWP1:CRBN:DDB1 in complex with NSD2-LDD, an LDD degrader
Method: EM (single particle) / Resolution: 3.1 Å

PDB-9y60:
Crystal structure of NSD2 PWWP1 domain in complex with (6R)-6-(3,5-dichlorophenyl)morpholin-3-one (ligand 2)
Method: X-RAY DIFFRACTION / Resolution: 2.023 Å

Chemicals

PDB-1csp:
CRYSTAL STRUCTURE OF THE BACILLUS SUBTILIS MAJOR COLD SHOCK PROTEIN, CSPB: A UNIVERSAL NUCLEIC-ACID BINDING DOMAIN

ChemComp-HOH:
WATER

PDB-1csq:
CRYSTAL STRUCTURE OF THE BACILLUS SUBTILIS MAJOR COLD SHOCK PROTEIN, CSPB: A UNIVERSAL NUCLEIC-ACID BINDING DOMAIN

ChemComp-ZN:
Unknown entry

Source
  • homo sapiens (human)
KeywordsTRANSFERASE / NSD2 / PWWP1 / binder / methyltransferase / LIGASE / Cereblon / degrader / DDB1 / LDD

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