CD56-OVEREXPRESSING MYELOMA CELLS ARE MORE VULNERABLE TO NAD+ EXHAUSTING STRATEGIES DUE TO DEPENDENCY ON CD38 ENZYMATIC ACTIVITY

CD56, also known as NCAM1 (Neural Cell Adhesion Molecule 1), is a member of the immunoglobulin superfamily and is deregulated in many tumors including Multiple Myeloma (MM) where it is expressed on the surface of malignant plasma cells in almost 70% of patients. This glycoprotein, as previously reported, seems to have several functions, including role in adhesion, tumor growth and response to therapy. However, studies are required to fully elucidate its biological role in MM. In this study, we analyzed CD56 surface levels on malignant plasma cells collected from our cohort of MM patients at Saint Martin Policlinic Hospital, Genoa, Italy. We confirmed that low CD56 expression correlates with extramedullary disease (EMD), while high CD56 levels are associated with a better prognosis. Additionally, we observed a positive correlation between CD56 and CD38, another therapeutic target in MM, in both patients and MM cell lines. Given the clinical significance of this correlation, we investigated the sensitivity of different cell lines and MM patients’ cells with high CD56 expression to the anti-CD38 monoclonal antibodies (moAbs). An increased sensitivity to these therapies was observed in this subgroup. Since CD38 acts as an ecto-enzyme that depletes NAD+, we observed higher CD38 enzymatic activity and lower intracellular NAD+ levels in CD56 overexpressing MM cells. This led us to speculate a potential role for CD56 in the NAD+ biosynthesis pathway. Indeed, we observed that CD56 overespressing cells are more sensitive to NAD+ lowering agents, such as NAMPT inhibitors. In conclusion, this study highlights the importance of immunophenotypic analysis of bone marrow plasma cells to guide personalized treatment strategies for MM patients. These findings suggest that therapies incorporating anti-CD38 antibodies and/or NAMPT inhibitors may be particularly effective for MM patients with high CD56 expression on bone marrow plasma cells (BMPCs).