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Multiple myeloma (MM) patients harboring the t(4;14) chromosomal translocation overexpress the histone methyltransferase NSD2, which drives a high-risk, aggressive disease phenotype. The discovery of a selective NSD2-ligand-directed degrader (NSD2-LDD) enables potent elimination of oncogenic NSD2 isoforms, reversing aberrant epigenomic programs. NSD2-LDD treatment disrupts MM-associated phenotypes including niche interactions and tumor growth, extending survival in preclinical t(4;14) models and representing a promising targeted therapeutic approach for this poor-prognosis subgroup.
