SETDB1 suppresses interferon responses and NK cell-mediated immunosurveillance specifically in monocytic AML: Gene expression profiles of cSAM leukemia cells with Setdb1 depletion [RNA-seq]

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 was mainly dependent on NK cell-mediated cytotoxicity. Mechanistically, SETDB1 depletion upregulated interferon-stimulated genes and NKG2D ligands through demethylation of histone H3 Lys9 at the monocyte-specific enhancer regions, thereby enhancing their immunogenicity to NK cells and intrinsic apoptosis. Importantly, these effects were not observed in non-monocytic leukemia cells. We also identified the expression of MNDA and its murine counterpart Ifi203 as biomarkers to predict the sensitivity of each AML to SETDB1 depletion. Our study highlights the critical and selective role of SETDB1 in monocytic AML and underscores its potential as a therapeutic target for current unmet needs. To assess the molecular changes induced by Setdb1 depletion in mouse cSAM leukemia cells (transformed by SETBP1 and ASXL1 mutations), we examined gene expression profiles of cSAM cells with non-targeting control or Setdb1-targeting sgRNA by RNA-seq. cSAM cells were transduced with sgRNA (coexpress puromycin) plasmids and performed bulk RNA-seq after 1 µg/ml puromycin selection for 4 days.