GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE328nnn/GSE328215/primaryOK200GenomicsHomo sapiensGenome binding/occupancy profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE328215GEOGSEfalseNSD2 Degradation Remediates the Oncogenic Cistrome in t(4;14) Multiple Myeloma [ATAC-seq]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. 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 and 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. 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.2026/07/15GSE328215GSM9675120GSM9675131GSM9675130GSM9675133GSM9675122GSM9675132GSM9675121GSM9675135GSM9675124GSM9675134GSM9675123GSM9675126GSM9675137GSM9675136GSM9675125GSM9675139GSM9675128GSM9675138GSM9675127GSM9675119GSM9675129GSM967511830173328215Homo sapiens[42371798]