Epigenetic regulation of NK cell-mediated immune response in multiple myeloma [ChIP-Seq]
Anti-CD38 monoclonal antibodies like Daratumumab (Dara) are effective in multiple myeloma (MM); however, drug resistance ultimately occurs and the mechanisms behind this are poorly understood. Here, we performed two in vitro genome-wide CRISPR screens to systematically discover the regulators of sensitivity to Dara-mediated antibody-dependent cellular cytotoxicity (ADCC) and identified KDM6A. The loss of KDM6A led to a marked downregulation in CD38 expression by increasing H3K27me3 on the CD38 promoter, resulting in resistance to Dara-mediated ADCC. Yet, adding back CD38 did not completely rescue this phenotype. In fact, KDM6A loss also downregulated CD48, which promoted Dara resistance by inhibiting natural killer cell activity. Lowering the H3K27me3 with an EZH2 inhibitor restored sensitivity to Dara through CD38 and CD48 upregulation. These findings suggest KDM6A loss as a mechanism of Dara resistance and explore the strategy of using an EZH2 inhibitor, one of which is already FDA-approved, to improve the response to Dara in MM. Overall design: Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for the histone modification H3K27me3 in H929 control and KDM6A KO cells