IRF2BP2-mediated MHC-I expression controls cytotoxic T cell responses in acute myeloid leukemia [ChIP-Seq]
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ABSTRACT:
PROVIDER: PRJNA1052131 | ENA |
REPOSITORIES: ENA
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Project description:Immunotherapy, including immune checkpoint blockade (ICB), has become an effective option for treating patients with cancer, especially those with solid tumors. Recently, T cell-based cellular therapies have extended the scope of immunotherapy to B-cell malignancies. Immunotherapy options for patients with acute myeloid leukemia (AML), however, are limited. To identify new immunotherapy approaches for AML, we performed CRISPR/Cas9 AML T cell co-culture screens. We determined that depletion of the transcription factor IRF2BP2 leads to enhanced T cell killing both in vitro and in vivo. Gene expression profiling and flow cytometry studies confirmed enhanced MHC-I expression upon IRF2BP2 loss. Chromatin binding analysis further revealed a regulatory axis whereby MHC-I expression is repressed by IRF2BP2 through its repression of the interferon alpha pathway. Our studies have identified the inhibition of IRF2BP2 as a potential strategy for enhancing T-cell-based therapies in patients with AML
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Project description:Immunotherapy, including immune checkpoint blockade (ICB), has become an effective option for treating patients with cancer, especially those with solid tumors. Recently, T cell-based cellular therapies have extended the scope of immunotherapy to B-cell malignancies. Immunotherapy options for patients with acute myeloid leukemia (AML), however, are limited. To identify new immunotherapy approaches for AML, we performed CRISPR/Cas9 AML T cell co-culture screens. We determined that depletion of the transcription factor IRF2BP2 leads to enhanced T cell killing both in vitro and in vivo. Gene expression profiling and flow cytometry studies confirmed enhanced MHC-I expression upon IRF2BP2 loss. Chromatin binding analysis further revealed a regulatory axis whereby MHC-I expression is repressed by IRF2BP2 through its repression of the interferon alpha pathway. Our studies have identified the inhibition of IRF2BP2 as a potential strategy for enhancing T-cell-based therapies in patients with AML
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Project description:IRF2BP2-mediated MHC-I expression controls cytotoxic T cell responses in acute myeloid leukemia
| PRJNA1052128 | ENA
Project description:IRF2BP2-mediated MHC-I expression controls cytotoxic T cell responses in acute myeloid leukemia [RNA-Seq]
| PRJNA1052127 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
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Project description:Acute myeloid leukemia (AML) is a hematological malignancy characterized by the abnormal proliferation and accumulation of immature myeloid cells in the bone marrow. Inflammation plays a crucial role in AML progression, but excessive activation of inflammatory pathways can also trigger cell death. IRF2BP2 is a chromatin regulator that has been implicated in AML pathogenesis, although its precise role in this disease is not fully understood. In this study, we demonstrate that in AML cells IRF2BP2 interacts with the transcriptional heterodimer ATF7/JDP2, which is involved to activate inflammatory pathways in AML cells. We show that IRF2BP2 is recruited by the ATF7/JDP2 dimer to chromatin and counteracts its gene activating function. Loss of IRF2BP2 leads to the overactivation of inflammatory pathways, resulting in immediate cell death. Our findings suggest that a delicate balance of activating and repressive transcriptional mechanisms establishes a pro-oncogenic inflammatory set-up in AML cells, and that manipulation of the ATF7/JDP2-IRF2BP2 regulatory axis may offer a potential vulnerability for AML treatment. Thus, our study provides new insights into the molecular mechanisms underlying AML pathogenesis and identifies a potential therapeutic target for AML treatment.
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Project description:Interferon regulatory factor 2 binding protein 2 (Irf2bp2), a co-repressor of Irf2, is required for fetal hepatic erythropoiesis through the expansion of erythromyeloid progenitors. Mice with germline ablation of the entire Irf2bp2 transcript produced no viable Irf2bp2-null (knockout, KO) pups in first litters. In subsequent litters, fewer than 1/3 of the expected KO pups were born and half survived to adulthood. Heart, skeletal muscle and liver tissues (tissues with high Irf2bp2 expression) were acquired from WT and KO mice, followed by RNA extraction using the RNeasy Midi Kit and subsequent gene expression profiling using the Affymetrix Mouse Gene 1.0 ST v1 array. Transcriptome profiles of surviving KO mice were contrasted to WT mice giving insight to modified gene expression in the absence of Irf2bp2 across multiple vital tissues.
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Project description:We report a previously unrecognized role of IRF2BP2 in neuroblastoma. To explore IRF2BP2-dependent gene regulation, RNA-seq analysis was conducted and the differently expressed genes were revealed in the IRF2BP2-knockdown SK-N-BE(2) cells in comparison to control group. We find that IRF2BP2 contributes to maintenance ADRN signature of neuroblastoma cell.
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Project description:Acute myeloid leukemia (AML) is a hematological malignancy characterized by abnormal proliferation and accumulation of immature myeloid cells in the bone marrow. Inflammation plays a crucial role in AML progression, but excessive activation of cell-intrinsic inflammatory pathways can also trigger cell death. IRF2BP2 is a chromatin regulator implicated in AML pathogenesis, although its precise role in this disease is not fully understood. In this study, we demonstrate that IRF2BP2 interacts with the AP-1 heterodimer ATF7/JDP2, which is involved in activating inflammatory pathways in AML cells. We show that IRF2BP2 is recruited by the ATF7/JDP2 dimer to chromatin and counteracts its gene-activating function. Loss of IRF2BP2 leads to overactivation of inflammatory pathways, resulting in strongly reduced proliferation. Our research indicates that a precise equilibrium between activating and repressive transcriptional mechanisms creates a pro-oncogenic inflammatory environment in AML cells. The ATF7/JDP2-IRF2BP2 regulatory axis is likely a key regulator of this process and may, therefore, represent a promising therapeutic vulnerability for AML. Thus, our study provides new insights into the molecular mechanisms underlying AML pathogenesis and identifies a potential therapeutic target for AML treatment.
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Project description:Acute myeloid leukemia (AML) is a hematological malignancy characterized by abnormal proliferation and accumulation of immature myeloid cells in the bone marrow. Inflammation plays a crucial role in AML progression, but excessive activation of cell-intrinsic inflammatory pathways can also trigger cell death. IRF2BP2 is a chromatin regulator implicated in AML pathogenesis, although its precise role in this disease is not fully understood. In this study, we demonstrate that IRF2BP2 interacts with the AP-1 heterodimer ATF7/JDP2, which is involved in activating inflammatory pathways in AML cells. We show that IRF2BP2 is recruited by the ATF7/JDP2 dimer to chromatin and counteracts its gene-activating function. Loss of IRF2BP2 leads to overactivation of inflammatory pathways, resulting in strongly reduced proliferation. Our research indicates that a precise equilibrium between activating and repressive transcriptional mechanisms creates a pro-oncogenic inflammatory environment in AML cells. The ATF7/JDP2-IRF2BP2 regulatory axis is likely a key regulator of this process and may, therefore, represent a promising therapeutic vulnerability for AML. Thus, our study provides new insights into the molecular mechanisms underlying AML pathogenesis and identifies a potential therapeutic target for AML treatment.
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