NSD2 Degradation Remediates the Oncogenic Cistrome in t(4;14) Multiple Myeloma
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.
Authors
- Diana Anderson (ORCID: https://orcid.org/0000-0001-9673-0398)
- S.A. Johnson (ORCID: https://orcid.org/0000-0002-0244-5201)
- Neil Bence (ORCID: https://orcid.org/0000-0002-6723-2880)
- José A. Martínez-Climent (ORCID: https://orcid.org/0000-0002-7938-3950)
- Marta Larráyoz (ORCID: https://orcid.org/0000-0001-6097-8244)
- Patrick R. Hagner (ORCID: https://orcid.org/0000-0002-8577-0105)
- Andy Christoforou (ORCID: https://orcid.org/0000-0002-3933-1793)
- Kyle Hess (ORCID: https://orcid.org/0000-0003-2096-0626)
- Rama Krishna Narla (ORCID: https://orcid.org/0000-0001-5181-3376)
- Antonia Lopez‐Girona (ORCID: https://orcid.org/0009-0009-1306-7021)
- J. Zhu (ORCID: https://orcid.org/0000-0001-5436-4262)
- Anita K. Gandhi (ORCID: https://orcid.org/0000-0001-5512-1625)
- Bo Hu (ORCID: https://orcid.org/0000-0001-8527-3750)
- Diana Jankeel (ORCID: https://orcid.org/0009-0005-8998-3078)
- Mark Rolfe (ORCID: https://orcid.org/0009-0001-7585-2684)
- Preethi Janardhanan (ORCID: https://orcid.org/0000-0003-3719-7938)
- Nicholas Stong (ORCID: https://orcid.org/0000-0002-0678-637X)
- J Edwards
- Sophie X. Peng (ORCID: https://orcid.org/0009-0004-9268-8195)
- Gauri Deb (ORCID: https://orcid.org/0000-0003-3559-1595)
- Deborah S. Mortensen (ORCID: https://orcid.org/0000-0002-9144-0962)
- Chad C. Bjorklund (ORCID: https://orcid.org/0000-0002-5965-3263)
- Yue Ren (ORCID: https://orcid.org/0000-0003-4281-358X)
- Jim Gamez
- Celia Fontanillo
- Lynda Groocock
- Hardik Modi
- Oscar Enrique Echeagaray
- Jim Leisten
Institutions
- Bristol-Myers Squibb (Germany) (DE)
- Eli Lilly (United States) (US)
- Bristol-Myers Squibb (United States) (US)
- Bristol-Myers Squibb (Sweden) (SE)
- Universidad de Navarra (ES)
Publication Details
- Journal
- Blood
- Published
- 2026-06-29
- DOI
- https://doi.org/10.1182/blood.2025031998
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 0.00