Speaker: Michael Tomasson, professor of medicine, health and human physiology and director of Integrative Pathophysiology and Genetics Laboratory at the University of Iowa

Title: Nuclear Receptor Binding SET Domain Protein 2 (NSD2) gene

Abstract: NSD2 (MMSET) encodes a histone di-methyltransferase (H3K36me2) and is activated in at least 15 cancer types. The primary resulting product, H3K36me2, assumes pivotal roles in various cellular processes, including transcription process, epigenetic regulation, interactions with other epigenetic modifications, cancer pathogenesis, and DNA damage repair. NSD2 activation through translocation, mutation, or overexpression occurs in both hematological and solid malignancies, including high-risk multiple myeloma (MM). NSD2 has been recognized to play a role in erythroid differentiation and B cell development. Strong evidence supports NSD2 as a driver mutation, with its activation recapitulating an oncogenic phenotype in cell culture and mice. NSD2 activation involves multiple oncogenic pathways and contributes to cancer pathogenesis and metabolism. 

MM cells harboring the t(4;14) (p16; q32) chromosomal translocation ectopically express NSD2 under the control of the B lineage-specific 5’ immunoglobulin enhancer, resulting in activation of oncogenic pathways and is associated pathogenetically with plasma cell dyscrasias (Monoclonal Gammopathy of Uncertain Significance, MGUS, smoldering multiple myeloma, and malignant multiple myeloma). The non-coding small nucleolar RNA (snoRNA) ACA11 is encoded in the intron 18 of NSD2 and is co-transcriptionally co-expressed with the mRNA of NSD2. Separately, over-expression of snoRNA ACA11 suppresses the NRF2 oxidative stress response, leading to increased levels of reactive oxygen species, increased ribosomal biogenesis, and increased cell proliferation. 

Host: Raquel Espin Palazon, genetics, development and cell biology assistant professor