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December 8, 2025Blood

NSD2 expression remodels DNA methylation, creating a targetable epigenetic dependency in t(4;14) multiple myeloma

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Authors

DPDoris R. PowellAWArun P. WiitaCMConstantine S. Mitsiades

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Overview

Analysis reveals that NSD2 overexpression heightens sensitivity to hypomethylating agents in multiple myeloma, suggesting new treatment strategies.

Key Points

  • Examine how NSD2 influences DNA methylation and treatment sensitivity in t(4;14) multiple myeloma.
  • Analyzed primary multiple myeloma samples using Whole Genome Bisulfite Sequencing.
  • Utilized CRISPR/Cas9 to ablate NSD2 in cell lines KMS11 and KMS18 for comparison.
  • Evaluated cell responses to decitabine and GSK-3685032 using flow cytometry for apoptosis identification.
  • Conducted RNAseq to identify differentially expressed genes after treatment with DAC.
  • Higher DNA methylation levels were observed in t(4;14) MM associated with NSD2 overexpression.
  • NSD2-high cells showed greater sensitivity to DNA methylation inhibition by decitabine compared to NSD2-low cells.
  • RNAseq analysis indicated significant expression changes associated with cell cycle and interferon response after DAC treatment.

Cite This Study

Powell et al. (2025) studied this question.

synapsesocial.com/papers/69362f514fa91c937236d953https://doi.org/10.1182/blood-2025-572
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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. 3Inhibition of NSD2 in t(4;14) myeloma induces changes in mitochondrial priming2025
  4. 4Abstract 7058: NSD2 overexpression drives multiple myeloma dependence on adenylate kinase 2 by diverting one-carbon metabolism to the epigenome2024
  5. 5NSD2 Degradation Remediates the Oncogenic Cistrome in t(4;14) Multiple Myeloma2026