Abstract 2783 Pleiotropic Effects of Chromatin Deregulation by NSD2 in Hematological Malignancies

NSD2 is a histone methyltransferase (HMT) that catalyzes histone H3 lysine 36 dimethylation (H3K36me2), opposing the Polycomb 2 complex (PRC2) and its HMT enzyme EZH2, which generates H3 lysine 27 trimethylation (H3K27me3). NSD2 contains the enzymatic SET domain and chromatin-binding HMG, PWWP, and PHD domains, recognizing marks like H3K36me3 and H3K27me3. NSD2 is highly overexpressed in ∼15% of multiple myeloma (MM) cases linked to translocation (4;14), a high-risk form of the disease. Activating mutations (e.g., E1099K, T1150A) are seen in acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL), and less frequently in MM and solid tumors such as colon cancer and glioblastoma.