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 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.