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

Monocytic acute myeloid leukemia (AML) responds poorly to current treatments, including venetoclax-based therapy. We conducted in vivo and in vitro CRISPR-Cas9 library screenings using a mouse monocytic AML model and identified SETDB1 and its binding partners (ATF7IP and TRIM33) as crucial tumor promoters in vivo. The growth-inhibitory effect of Setdb1 depletion in vivo is dependent mainly on natural killer (NK) cell-mediated cytotoxicity. Mechanistically, SETDB1 depletion upregulates interferon-stimulated genes and NKG2D ligands through the demethylation of histone H3 Lys9 at the enhancer regions, thereby enhancing their immunogenicity to NK cells and intrinsic apoptosis. Importantly, these effects are not observed in non-monocytic leukemia cells. We also identified the expression of myeloid cell nuclear differentiation antigen (MNDA) and its murine counterpart Ifi203 as biomarkers to predict the sensitivity of AML to SETDB1 depletion. Our study highlights the critical and selective role of SETDB1 in AML with granulo-monocytic differentiation and underscores its potential as a therapeutic target for current unmet needs. [Display omitted] • CRISPR-Cas9 screens identify SETDB1 and its cofactors as tumor promoters in vivo • SETDB1 mediates H3K9me3 at the ERV enhancers to repress inflammation and NKG2D ligands • SETDB1 depletion in granulo-monocytic AMLs enhances their sensitivity to NK cell response Chang et al. perform CRISPR-Cas9 library screens and identify SETDB1 and its binding partners as key players in suppressing the NK cell-mediated immune surveillance against acute myeloid leukemia with granulocytic and monocytic differentiation, highlighting SETDB1 as a selective and promising therapeutic target in this disease. [ABSTRACT FROM AUTHOR]