SETDB1 suppresses NK cell-mediated immunosurveillance in acute myeloid leukemia with granulo-monocytic differentiation

• DOI: 10.1016/j.celrep.2024.114536
• Publication Date: 2024-08-02T14:37:16Z
• Authors: Yu-Hsuan Chang; Keita Yamamoto; Takeshi Fujino; Teh-Wei Wang; Emi Sugimoto; Wenyu Zhang; Tomohiro Yabushita; Ken Suzaki; E. Christine Pietsch; Barbara A. Weir; Ramona Crescenzo; Glenn S. Cowley; Ricardo Attar; Ulrike Philippar; Mark Wunderlich; Benjamin Mizukawa; Yi Zheng; Yutaka Enomoto; Yoichi Imai; Toshio Kitamura; Susumu Goyama
• Keywords: Acute monocytic leukemia; Immunosurveillance; Plasmacytoid dendritic cell

Monocytic acute myeloid leukemia (AML) responds poorly to current treatments, including venetoclax-based therapy. We conducted in vivo and vitro CRISPR-Cas9 library screenings using a mouse monocytic AML model identified SETDB1 its binding partners (ATF7IP TRIM33) as crucial tumor promoters vivo. The growth-inhibitory effect of Setdb1 depletion is dependent mainly on natural killer (NK) cell-mediated cytotoxicity. Mechanistically, upregulates interferon-stimulated genes NKG2D ligands through the demethylation histone H3 Lys9 at enhancer regions, thereby enhancing their immunogenicity NK cells intrinsic apoptosis. Importantly, these effects are not observed non-monocytic cells. also expression cell nuclear differentiation antigen (MNDA) murine counterpart Ifi203 biomarkers predict sensitivity depletion. Our study highlights critical selective role with granulo-monocytic underscores potential therapeutic target for unmet needs.