Pathogenic Mechanisms Activated by NSD2 Translocations in Multiple Myeloma

The NSD2 gene is overexpressed in multiple cancers and is associated with cancer cell proliferation, invasion, and metastasis. NSD2 gene is universally present in multiple myeloma (MM) patients with t(4;14) (p16;q32) translocation, a high-risk subtype. NSD2 is characterized by different breakpoints. NSD2Δ3 breakpoint is associated with shorter survival than other breakpoints. NSD2Δ3 contains non-coding RNA ACA11 within intron 18. Additionally, 80% of t(4;14) MM patients lack the retinoblastoma tumor suppressor gene (RB1). We hypothesize that ACA11 cooperates with RB1 loss in MM pathogenesis. Also, we hypothesize that NSD2Δ3 increases protein expression driving myeloma growth. To overexpress NSD2 WT , snoACA11, and NSD2Δ3 in cells, we cloned NSD2 WT , and NSD2Δ3 plasmid constructs in a murine stem cell virus (MSCV)-IRES- GFP vector. We isolated primary B cells from RB1 wild-type and knock-out mice by CD43 microbeads and transduced those cells using a virus containing ACA11 and NSD2 WT . ACA11 overexpression significantly increased B cell proliferation in Rb1dKO mice. This hyperproliferative phenotype is induced by reactive oxygen species (ROS) levels. However, we did not find a further increase in B cell proliferation with co-overexpression of NSD2 WT and ACA11 in Rb1dKO mice. We demonstrated increased protein stability by finding higher NSD2Δ3 protein expression compared to NSD2 WT protein expression in HEK293T cells. These results support our hypothesis and demonstrate oncogenic role of ACA11 in t(4;14) MM. Future work will be done to determine the cell biological effects of NSD2Δ3 and establish its role in myeloma pathogenesis. Completion of this study will advance understanding of this epigenetic NSD2 gene and potentially develop targeted drugs for NSD2, providing more individualized treatment options for these patients. University of Iowa Department of Internal Medicine. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.