Epigenetic regulation of CD38/CD48 by KDM6A mediates NK cell response in multiple myeloma

Jiye Liu, Lijie Xing, Jiang Li, Kenneth Wen, Ning Liu, Yuntong Liu, Gongwei Wu, Su Wang, Daisuke Ogiya, Tian-Yu Song, Keiji Kurata, Johany Penailillo, Eugenio Morelli, Tingjian Wang, Xiaoning Hong, Annamaria Gulla, Yu-Tzu Tai, Nikhil Munshi, Paul Richardson, Ruben Carrasco, Teru Hideshima and Kenneth C. Anderson ()
Additional contact information
Jiye Liu: Dana-Farber Cancer Institute
Lijie Xing: Shandong First Medical University and Shandong Academy of Medical Sciences
Jiang Li: The Seventh Affiliated Hospital of Sun Yat-Sen University
Kenneth Wen: Dana-Farber Cancer Institute
Ning Liu: Dana-Farber Cancer Institute
Yuntong Liu: Dana-Farber Cancer Institute
Gongwei Wu: Dana-Farber Cancer Institute
Su Wang: Vertex pharmaceuticals
Daisuke Ogiya: Tokai University
Tian-Yu Song: Dana-Farber Cancer Institute
Keiji Kurata: Dana-Farber Cancer Institute
Johany Penailillo: Dana-Farber Cancer Institute
Eugenio Morelli: Dana-Farber Cancer Institute
Tingjian Wang: Dana-Farber Cancer Institute
Xiaoning Hong: The Seventh Affiliated Hospital of Sun Yat-Sen University
Annamaria Gulla: Dana-Farber Cancer Institute
Yu-Tzu Tai: Dana-Farber Cancer Institute
Nikhil Munshi: Dana-Farber Cancer Institute
Paul Richardson: Dana-Farber Cancer Institute
Ruben Carrasco: Dana-Farber Cancer Institute
Teru Hideshima: Dana-Farber Cancer Institute
Kenneth C. Anderson: Dana-Farber Cancer Institute

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract 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 identify, via two in vitro genome-wide CRISPR screens probing Daratumumab resistance, KDM6A as an important regulator of sensitivity to Daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Loss of KDM6A leads to increased levels of H3K27me3 on the promoter of CD38, resulting in a marked downregulation in CD38 expression, which may cause resistance to Daratumumab-mediated ADCC. Re-introducing CD38 does not reverse Daratumumab-mediated ADCC fully, which suggests that additional KDM6A targets, including CD48 which is also downregulated upon KDM6A loss, contribute to Daratumumab-mediated ADCC. Inhibition of H3K27me3 with an EZH2 inhibitor resulted in CD38 and CD48 upregulation and restored sensitivity to Daratumumab. These findings suggest KDM6A loss as a mechanism of Daratumumab resistance and lay down the proof of principle for the therapeutic application of EZH2 inhibitors, one of which is already FDA-approved, in improving MM responsiveness to Daratumumab.

Date: 2024
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DOI: 10.1038/s41467-024-45561-z

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