Dr Liu on Epigenetic Regulation of CD38/CD48 in Multiple Myeloma

Jiye Liu, PhD, instructor in medicine, Department of Medicine, Dana-Farber Cancer Institute, discusses epigenetic regulation of CD38/CD48 in multiple myeloma.

Daratumumab (Darzalex) is an anti-CD38 monoclonal antibody used in the treatment of patients with newly diagnosed and relapsed/refractory multiple myeloma. To better understand resistance to daratumumab, investigators first performed a 2-cell type genome-scale CRISPR-Cas9 knockout screening to determine the genes that are associated with daratumumab-mediated cytotoxicity.

Results presented during the 2023 International Myeloma Society Annual Meeting showed that inactivation of KDM6A was shown to strongly downregulate CD38 and CD48 expression through H3K27me3 regulation, inhibiting the antibody-dependent cell-mediated cytotoxicity of daratumumab. Moreover, investigators showed a reduction in the activity of natural killer cells, Liu says. Notably, CD38 expression was restored when KDM6A was reintroduced to KDM6A knockout cells—but only partially, Liu explains.

Because KDM6A opposes the EZH2 gene in the PRC2 complex through H3K27me3 demethylation, investigators tested the ability of the EZH2 inhibitor tazemetostat (Tazverek) to increase H3K27me3 levels and upregulate expression in CD38 and CD48.

Notably, treatment with the EZH2 inhibitor was shown to upregulate CD38 and CD48 expression and enhance daratumumab-mediated antibody-dependent cell-mediated cytotoxicity, both in vitro and in vivo, Liu concludes.