Abstract 319: Syntenin regulates multiple myeloma cell survival

Abstract

Abstract Multiple myeloma is the second most common hematological malignancy with an estimated 30,000 new diagnoses in 2017. Myeloma cells retain numerous characteristics of normal plasma cells including reliance on survival signals in the bone marrow for long term viability. However, they have gained the capacity to proliferate, causing harmful bone lesions in patients, and in advanced stages become extramedullary. Therefore, we are investigating molecular mechanisms of myeloma cells that allow them to survive independently of the bone marrow microenvironment. We have identified syntenin as a protein involved in myeloma cell survival and a potential therapeutic target. Syntenin has been reported to bind to and regulate levels of the plasma cell marker, CD138. We used the CoMMpass dataset, a longitudinal study of myeloma patients following their transcriptomic expression throughout treatment, and discovered that patients expressing in the top quartile for syntenin trend toward lower overall survival, progression-free survival, and shorter response duration than those in the bottom quartile. To determine whether it is involved in myeloma cell survival, we used short hairpin RNA to knock down syntenin (shsyn) in RPMI 8226 and MM1.s myeloma cell lines and determined cell death using Annexin-V staining four days following lentiviral infection. We observed increased death in syntenin-silenced cells compared to our empty vector control in both RPMI 8226 (control=57.83% viable, shsyn=29.47% viable, p=0.04) and MM1.s cell lines (control=91.43% viable, shsyn=70.1% viable, p=0.04) suggesting that syntenin is important for myeloma cell survival. Syntenin is a PDZ-domain containing protein that has been shown to regulate expression of several transmembrane proteins. We, therefore, wanted to look at correlation of syntenin expression with CD138 and CD86, two PDZ-binding domain containing proteins expressed on the surface of myeloma cells. Using the CoMMpass dataset, we found patients with high expression of syntenin had increased expression of CD86 while syntenin-low patients had decreased CD86 expression. This correlation does not exist with CD138 as syntenin-low patients express higher levels of CD138. The correlation with CD86 but not CD138 suggests a previously undescribed role for syntenin in myeloma cells. Our lab has shown that expression of CD86 is necessary for myeloma cell survival, and signals to confer drug resistance. When we silenced syntenin, we observed decreased CD86 expression. Moreover, knockdown of CD86 showed increased expression of syntenin. Taken together, these data suggest that syntenin may regulate CD86 expression on the cell surface. We now show a novel role for syntenin in myeloma cell viability and as a potential regulator of CD86 expression. Syntenin has not previously been explored in multiple myeloma and determining its molecular function is warranted as it may be an effective target for therapeutic treatment of the disease. Citation Format: Tyler Moser-Katz, Catherine M. Gavile, Benjamin G. Barwick, Sagar Lonial, Lawrence H. Boise. Syntenin regulates multiple myeloma cell survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 319.