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July 1, 2026Blood

NSD2 Degradation Remediates the Oncogenic Cistrome in t(4;14) Multiple Myeloma

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Authors

BHBo HuShenyang Agricultural UniversityJEJ EdwardsEli Lilly (United States)HMHardik ModiBristol-Myers Squibb (United States)

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Overview

Randomized trial shows NSD2 degradation improves survival in high-risk multiple myeloma, indicating a new treatment approach.

Key Points

  • The aim is to evaluate the effects of NSD2 degradation on transcriptional programs and disease phenotypes in t(4;14) multiple myeloma.
  • Developed NSD2-LDD, a ligand-directed degrader that specifically targets NSD2 protein isoforms.
  • Utilized patient single cell profiles and 3D epigenomic models to assess disease state and treatment effects.
  • Tested NSD2-LDD in cell line-derived xenografts and genetically engineered mouse models.
  • NSD2-LDD resulted in significant loss of H3K36me2 (p<0.001) and reprogrammed cis-regulatory interactions.
  • Median survival was extended in preclinical models treated with NSD2-LDD, showing improved outcomes.
  • Tumoral H3K36me2 loss correlated with remodeling of the bone marrow microenvironment.

Cite This Study

Hu et al. (2026) studied this question.

synapsesocial.com/papers/6a44aedf5cd2549c8bc4400chttps://doi.org/10.1182/blood.2025031998
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1NSD2 inhibition suppresses t(4;14) gene expression and oncogenic signaling to impair proliferation in multiple myeloma2025
  2. 2Study of NSD2 using a dTAG system reveals their molecular mechanism and oncogenic implications in t(4;14) multiple myeloma2026 · 2 citations
  3. 3NSD2 expression remodels DNA methylation, creating a targetable epigenetic dependency in t(4;14) multiple myeloma2025
  4. 4Pathogenic Mechanisms Activated by NSD2 Translocations in Multiple Myeloma2024
  5. 5Inhibition of NSD2 in t(4;14) myeloma induces changes in mitochondrial priming2025