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Updated: Jun 18, 2025
Flow Cytometry-based Assay for the Monitoring of NK Cell Functions
Published on: October 30, 2016
SETDB1 suppresses NK cell-mediated immunosurveillance in acute myeloid leukemia with granulo-monocytic
Yu-Hsuan Chang1, Keita Yamamoto2, Takeshi Fujino2
1Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 108-8639, Japan; Division of Molecular Pharmacology of Malignant Diseases, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-8654, Japan.
Abstract:
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.
