Epigenetic regulation of CD38/48 by KDM6A mediates NK cell response in multiple myeloma (IMW 2023)
Introduction: Daratumumab (Dara) is a therapeutic antibody against CD38, which triggers both direct and immune-mediated cytotoxicity in multiple myeloma (MM) cells...KDM6A acts to oppose the EZH2/PRC2 complex by demethylating H3K27me3, and we found that Tazemetostat (Taze), an FDA-approved EZH2 inhibitor, increased the expression of CD38 and CD48 at the protein, mRNA, and surface expression levels, especially in KDM6A-KO cells... Taken together, our data reveal that KDM6A assists in Dara targeting by upregulating CD38 and in Dara cytotoxicity by modulating NK activity through CD48 regulation. By imitating its function using an FDA-approved inhibitor, we may overcome Dara resistance and improve patient outcomes in MM.