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NSD2 degradation remediates the oncogenic cistrome in t(4;14) multiple myeloma
Bo Hu1, Jacob Edwards2, Hardik Modi1
1Protein Homeostasis Thematic Research Center, Bristol Myers Squibb, San Diego, CA.
Abstract:
The t(4;14) chromosomal translocation drives overexpression of the histone methyltransferase NSD2 and defines a high-risk segment of patients with multiple myeloma (MM). Herein, we report the discovery of NSD2-ligand-directed degrader (NSD2-LDD), a cereblon-recruiting and PWWP1-mediated LDD that selectively and potently eliminates full-length and PWWP1 domain-containing NSD2 protein isoforms. NSD2-LDD treatment induces the global loss of H3K36me2, leading to promoter-proximal spreading of H3K27me3 and rewiring of cis-regulatory interactions that reverse t(4;14) transcriptional programs. These effects suppress MM disease-associated phenotypes, including stromal adhesion, 3-dimensional (3D) 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 remodeling. Although the NSD2-LDD response is restricted to PWWP1-containing models, collectively this work validates NSD2 as a tractable dependency and supports the clinical development of NSD2 degradation as a novel, targeted therapeutic strategy in high-risk MM.
Insights
A new drug, NSD2-LDD, effectively targets and degrades the NSD2 protein in high-risk multiple myeloma (MM) patients with the t(4;14) translocation. This targeted degradation reverses disease-specific gene expression and improves survival in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The t(4;14) chromosomal translocation is a key driver in a subset of multiple myeloma (MM) patients, leading to overexpression of the NSD2 histone methyltransferase.
- NSD2 overexpression contributes to aggressive disease phenotypes and poor prognosis in MM.
Purpose of the Study:
- To discover and characterize a novel therapeutic agent, NSD2-LDD, a ligand-directed degrader (LDD), for targeting NSD2 in t(4;14) multiple myeloma.
- To investigate the molecular mechanisms by which NSD2 degradation impacts MM cell biology and the tumor microenvironment.
Main Methods:
- Development of NSD2-LDD, a cereblon-recruiting LDD targeting NSD2 protein isoforms.
- Assessment of NSD2-LDD efficacy in cellular and in vivo models of t(4;14) MM, including xenografts and genetically engineered mouse models.
- Integration of patient single-cell profiling, 3D epigenomics, and spatial transcriptomics to understand disease state and therapeutic response.
Main Results:
- NSD2-LDD selectively degrades full-length and PWWP1 domain-containing NSD2 isoforms, inducing global loss of H3K36me2.
- Degradation of NSD2 reverses t(4;14) transcriptional programs, suppresses MM phenotypes (stromal adhesion, colony growth), and remodels the bone marrow microenvironment.
- NSD2-LDD treatment extends median survival in preclinical t(4;14) MM models, correlating with H3K36me2 loss and niche remodeling.
Conclusions:
- NSD2 is a druggable dependency in t(4;14) multiple myeloma.
- NSD2-LDD represents a promising novel therapeutic strategy for high-risk MM patients, warranting further clinical development.
