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

Cell Rep. 2024 Aug 27;43(8):114536. doi: 10.1016/j.celrep.2024.114536. Epub 2024 Aug 2.

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.

Keywords: CP: Cancer; CP: Molecular biology; NKG2D ligands; SETDB1; acute myeloid leukemia; anti-leukemic immunity; interferon-stimulated genes; natural killer cells.

MeSH terms

  • Animals
  • Apoptosis
  • Cell Differentiation*
  • Cell Line, Tumor
  • Histone-Lysine N-Methyltransferase* / genetics
  • Histone-Lysine N-Methyltransferase* / metabolism
  • Humans
  • Immunologic Surveillance
  • Killer Cells, Natural* / immunology
  • Killer Cells, Natural* / metabolism
  • Leukemia, Myeloid, Acute* / genetics
  • Leukemia, Myeloid, Acute* / immunology
  • Leukemia, Myeloid, Acute* / metabolism
  • Leukemia, Myeloid, Acute* / pathology
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / immunology
  • Monocytes / metabolism

Substances

  • Histone-Lysine N-Methyltransferase
  • SETDB1 protein, mouse
  • SETDB1 protein, human