Dr Sobh on the Effects of NSD2 Overexpression in Multiple Myeloma

“Our major finding so far is that we noticed that NSD2 over-expressing cells result in cell secreting something that can express MHC class II molecules on immune cells, and we believe that this will have immunosuppressive effects in an in vivo environment.”

Amin Sobh, PhD, a research assistant professor in the Division of Hematology/Oncology at the University of Florida College of Medicine, discussed findings from a study investigating the role that NSD2 plays in modulating immune surveillance in multiple myeloma.

NSD2 is a histone methyltransferase gene that is overexpressed in approximately 15% of patients with multiple myeloma harboring 4;14 translocations (t(4;14)), and overexpression of this gene may lead to immune evasion in tumors. Therefore, NSD2-mediated immune suppression may have therapeutic benefits in certain subsets of patients with this malignancy.

Based on this knowledge, Sobh and colleagues performed a multiomics analysis to investigate the role of NSD2 on immune surveillance in isogenic t(4;14) multiple myeloma cell lines with various NSD2 expression levels.

Preliminary findings from this study presented at the 2025 AACR Annual Meeting showed that NSD2 overexpression affects cell metabolism and metabolite secretion, Sobh said. Overexpression of NSD2 leads to both secretion of metabolites that can inhibit the immune system and inhibition of metabolites that can stimulate the immune system, he explained. NSD2 overexpression also leads to cell secretion of soluble factors that suppress MHC class II molecules on immune cells, which may have immunosuppressive effects in vivo and contribute to the aggressiveness of this disease subset, he reported.

Furthermore, flow cytometry demonstrated that genetic or pharmacological NSD2 disruption increased MHC-II expression levels. Additionally, cytokine profiling of human and murine myeloma cell lines showed that NSD2 inhibition suppressed production of interleukin-10, which is a known suppressor of MHC-II expression. Ongoing research in MOPC315.BM multiple myeloma mouse models may further demonstrate the effects of NSD2 on immune response.