Dr Sobh on Ongoing Investigations of NSD2 in Modulating Immune Surveillance in Myeloma

"We have done a lot of the in vitro components, but the next step would be working in a mouse model. We're trying to optimize the conditions. We had some challenges overexpressing NSD in mouse cells, but we're heading toward success with this model."

Amin Sobh, PhD, a research assistant professor in the Division of Hematology/Oncology at the University of Florida College of Medicine, discussed ongoing efforts to investigate the role of NSD2 expression in modulating immune surveillance in multiple myeloma, with a focus on the development of in vivo models to validate prior in vitro findings.

NSD2 is a histone methyltransferase that is frequently overexpressed in patients with multiple myeloma harboring the t(4;14) translocation. In addition to its role in driving oncogenic transcriptional programs, NSD2 has emerged as a potential contributor to immune evasion in the tumor microenvironment. Prior work has demonstrated that NSD2 overexpression could alter immune signaling and reduce tumor immunogenicity, highlighting it as a candidate therapeutic target.

Following completion of in vitro studies, such as the one presented by Sobh and colleagues at the 2025 AACR Annual Meeting, future research is aiming to establish a murine model of NSD2 overexpression to further explore its immunomodulatory effects in vivo. Although achieving stable overexpression of NSD2 in murine cells has been technically challenging, model optimization is ongoing, Sobh said. Once validated, the mouse model will be used to examine how NSD2-driven changes in myeloma cells affect immune recognition and clearance, he added.

In addition to characterizing the impact of NSD2 overexpression on immune surveillance, Sobh and colleagues plan to evaluate the efficacy of NSD2 inhibition in vivo. A selective NSD2 inhibitor currently in clinical development will be tested in these models to determine whether pharmacologic targeting of NSD2 can restore immune function and enhance antitumor responses. These investigations will also assess the downstream effects on immune cell activation and cytokine production.