NSD2 degradation remediates the oncogenic cistrome in t(4;14) multiple myeloma.

Degrading NSD2 with a targeted ligand degrader reverses oncogenic chromatin changes and improves survival in t(4;14) multiple myeloma models.

• Why it matters: High-risk multiple myeloma driven by t(4;14) translocation involves overexpression of NSD2, a key epigenetic regulator, making it a critical therapeutic target to improve patient outcomes.
• What they did: Researchers developed NSD2-LDD, a cereblon-recruiting degrader that selectively eliminates NSD2 isoforms containing the PWWP1 domain, and analyzed its effects through single-cell, epigenomic, and in vivo models.
• The result: NSD2-LDD treatment reduces H3K36me2, rewires gene regulation, suppresses tumor phenotypes, remodels the bone marrow microenvironment, and extends survival in mouse models, validating NSD2 as a promising therapeutic target.