“Our findings suggest a role for NSD2 in maintaining MM cell identity, with potential implications for future therapeutic strategies based on targeting of NSD2.”
BUFFALO, NY – April 2, 2025 – A new research paper was published in Oncotarget, Volume 16, on March 21, 2025, titled “NSD2-epigenomic reprogramming and maintenance of plasma cell phenotype in t(4;14) myeloma.”
Researchers Andrea Gunnell, Scott T. Kimber, Richard Houlston, and Martin Kaiser from The Institute of Cancer Research, London, studied how a gene called NSD2 affects the behavior of multiple myeloma (MM) cells. Their findings reveal that NSD2 plays a key role in helping cancer cells retain their identity as plasma cells—white blood cells that normally help the immune system fight infections. This discovery could shape future treatment strategies for patients with a high-risk form of MM known as t(4;14) myeloma.
Multiple myeloma is a type of blood cancer that begins in plasma cells found in the bone marrow. About 20% of patients have a genetic change called t(4;14), which makes the NSD2 gene highly active. The research team compared two types of myeloma cells: one with high NSD2 activity and one where NSD2 was turned off. They found that when NSD2 is active, it changes how DNA is folded and how genes are switched on or off, especially genes that help the cells act like plasma cells. When NSD2 was turned off, important markers like CD38 were reduced, and other genes normally silent in plasma cells were activated.
The study indicated that NSD2 does not directly affect the main genes responsible for plasma cell creation. Instead, it influences many other genes that help maintain the cancer cell’s identity, which contributes to cancer growth and survival.
The researchers also observed physical changes in the cancer cells. Cells with active NSD2 looked and behaved more like typical plasma cells, while cells without NSD2 appeared more immature and lost important surface markers. These changes were linked to differences in how the DNA was organized inside the cells.
These findings are especially important as new drugs are being developed to block NSD2. The study suggests that turning off NSD2 could change how MM cells respond to existing treatments. For example, if NSD2 is blocked and CD38 levels drop, the change might affect therapies that target CD38. However, the rise of other immune-related genes might make certain immunotherapies more effective.
“Identifying the biological consequences of NSD2 over-expression in MM is not only relevant to informing new therapeutic interventions through indirect targeting of downstream effectors, but also to anticipate possible consequences of targeting NSD2 directly.”
In summary, this study shows how NSD2 helps myeloma cells keep their cancerous identity by reorganizing the DNA and influencing gene activity. Understanding this role could help researchers design better treatment approaches and possibly overcome resistance to current therapies in t(4;14) myeloma.
Continue reading: DOI: https://doi.org/10.18632/oncotarget.28706
Correspondence to: Andrea Gunnell — andrea.gunnell@icr.ac.uk
Keywords: cancer, myeloma, NSD2, t(4;14), CD38, plasma cell
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