NSD2 Degradation Remediates the Oncogenic Cistrome in t(4;14) Multiple Myeloma
Abstract
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.
Article Details
Authors (29)
Bo Hu
Jacob Edwards
Hardik Modi
Bristol Myers Squibb, San Diego, California, United States
Jim Gamez
Bristol Myers Squibb, San Diego, California, United States
Oscar Enrique Echeagaray
Bristol Myers Squibb, San Diego, California, United States
Kyle Hess
Bristol Myers Squibb, San Diego, California, United States
Yue Ren
Diana Anderson
Bristol Myers Squibb, San Diego, California, United States
Marta Larrayoz
Jinyi Zhu
Scott Arne Johnson
Bristol Myers Squibb, San Diego, California, United States
Gauri Deb
Bristol Myers Squibb, San Diego, California, United States
Diana Jankeel
Bristol Myers Squibb, San Diego, California, United States
Preethi Janardhanan
Bristol Myers Squibb, San Diego, California, United States
Jim Leisten
Bristol Myers Squibb, San Diego, California, United States
Sophie Peng
Bristol Myers Squibb, San Diego, California, United States
Andy Christoforou
Bristol Myers Squibb, USA, California, United States
Nicholas Stong
Bristol Myers Squibb, Summit, New Jersey, United States
Celia Fontanillo
Bristol-Myers Squibb, San Diego, California, United States
Chad C Bjorklund
Bristol-Myers Squibb, Summit, New Jersey, United States
Patrick Ryan Hagner
Bristol-Myers Squibb, Summit, New Jersey, United States
Anita Krithivas Gandhi
Bristol-Myers Squibb, Madison, New Jersey, United States
Jose A Martínez-Climent
Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
Rama Krishna Narla
Bristol Myers Squibb, San Diego, California, United States
Antonia Lopez-Girona
Bristol-Myers Squibb, San Diego, California, United States
Mark Rolfe
Orbimed Advisors, Dillon Beach, California, United States
Neil Bence
Bristol Myers Squibb, San Diego, California, United States
Deborah S Mortensen
Bristol Myers Squibb, San Diego, California, United States
Lynda Groocock
Bristol Myers Squibb, San Diego, California, United States