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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]

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 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE266097 | GEO | 2024/08/03

REPOSITORIES: GEO

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SETDB1 suppresses interferon responses and NK cell-mediated immunosurveillance specifically in monocytic AML: H3K9me3 ChIP-seq of cSAM leukemia cells with Setdb1 depletion [ChIP-seq]

Project description: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.

2024-08-03 | GSE266098 | GEO

SETDB1 suppresses interferon responses and NK cell-mediated immunosurveillance specifically in monocytic AML: CRISPR/Cas9 screens on cSAM leukemia cells

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SETDB1 suppresses interferon responses and NK cell-mediated immunosurveillance specifically in monocytic AML: H3K9me3 ChIP-seq of cSAM leukemia cells with Setdb1 depletion [ChIP-seq]

Project description:SETDB1 suppresses interferon responses and NK cell-mediated immunosurveillance specifically in monocytic AML: H3K9me3 ChIP-seq of cSAM leukemia cells with Setdb1 depletion [ChIP-seq]

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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]

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Targeting the Atf7ip-Setdb1 complex augments anti-tumor immunity by boosting tumor immunogenicity

Project description:Despite substantial progress that has been made in understanding how tumors escape immune surveillance, measures to counteract tumor immune evasion have been limited. Suppression of tumor antigen expression is a common adaptive mechanism that cancers use to evade detection and destruction by the immune system. Epigenetic modifications play a critical role in in various aspects of immune invasion, including the regulation of tumor antigen expression. To identify novel epigenetic regulators of tumor antigen expression, we established a transplantable syngeneic tumor model of immune escape with silenced antigen expression and used this system as a platform for a CRISPR-Cas9 suppressor screen targeting genes encoding epigenetic modifiers. We found that genetic disruption of the chromatin modifiers Atf7ip or its interacting partner Setdb1 in tumor cells restored tumor antigen expression, resulting in augmented tumor immunogenicity concomitant with elevated endogenous retroviral antigens (ERVs), mRNA intron retention. ERVs disinhibition was associated with a robust type I interferon response and increased T cell infiltration, leading to rejection of cells lacking intact Atf7ip or Setdb1. ATF7IP or SETDB1 expression inversely correlated with antigen processing and presentation pathways, interferon signaling, and T cell infiltration and cytotoxicity in human cancers. Our results provide a rationale for targeting Atf7ip or Setdb1 in cancer immunotherapy.

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Transcriptomic and epigenomic profiling of SETDB1 mediated repression in Acute Myeloid Leukemia

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SETDB1 suppresses interferon responses and NK cell-mediated immunosurveillance specifically in monocytic AML: CRISPR/Cas9 screens on cSAM leukemia cells

Project description:SETDB1 suppresses interferon responses and NK cell-mediated immunosurveillance specifically in monocytic AML: CRISPR/Cas9 screens on cSAM leukemia cells

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Hypoxia stabilizes SETDB1 to maintain genome stability

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