Pbrm1 regulates interferon signaling in mouse AML [RNA-seq Mouse]
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ABSTRACT:
PROVIDER: PRJNA869700 | ENA |
REPOSITORIES: ENA
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Project description:Pbrm1 regulates interferon signaling in mouse AML
| PRJNA869695 | ENA
Project description:CRISPR/Cas9 screening approaches are powerful tools to identify in vivo cancer dependencies. Hematopoietic malignancies are genetically complex disorders in which sequential acquisition of somatic mutations generates clonal diversity. With time, additional cooperating mutations may drive disease progression. Using an in vivo pooled genetic mutagenesis screen of epigenetic factors in primary murine HSPCs, we sought to uncover unrecognized genes that contribute to leukemia progression. We first modeled myeloid leukemia in mice by functionally abrogating both Tet2 and Tet3 in HSPCs followed by transplantation. We then performed pooled mutagenesis of genes encoding epigenetic factors and identified Pbrm1/Baf180, a subunit of polybromo (PBAF) SWI/SNF chromatin remodeling complex, as a negative driver of disease progression. We found that Pbrm1 loss promoted leukemogenesis with significantly shortened latency. Pbrm1-deficient AML cells were less immunogenic, and characterized by attenuated interferon signaling and reduced MHC II expression. We explored potential relevance to human leukemia by assessing the involvement of Pbrm1 in control of interferon pathway components and found that Pbrm1 binds at promoters of a subset of these genes, and most notably at IRF1, which in turn regulates in MHC II expression. Our findings revealed a novel role of Pbrm1 in leukemia progression. More generally, CRISPR/Cas9 screening, coupled with phenotypic readouts in vivo, has revealed a pathway by which transcriptional control of interferon signaling influences leukemia cell interactions with the immune system.
2023-07-12 | GSE211260 | GEO
Project description:Pbrm1 regulates interferon signaling in mouse AML [RNA-seq HAP1]
| PRJNA869699 | ENA
Project description:Pbrm1 regulates interferon signaling in mouse AML [ChIP-seq HAP1]
| PRJNA869701 | ENA
Project description:CRISPR/Cas9 screening approaches are powerful tools to identify in vivo cancer dependencies. Hematopoietic malignancies are genetically complex disorders in which sequential acquisition of somatic mutations generates clonal diversity. With time, additional cooperating mutations may drive disease progression. Using an in vivo pooled gene editing screen of epigenetic factors in primary murine hematopoietic stem and progenitor cells (HSPCs), we sought to uncover unrecognized genes that contribute to leukemia progression. We first modeled myeloid leukemia in mice by functionally abrogating both Tet2 and Tet3 in HSPCs followed by transplantation. We then performed pooled CRISPR/Cas9 editing of genes encoding epigenetic factors and identified Pbrm1/Baf180, a subunit of polybromo BRG1/BRM-associated factor (PBAF) SWI/SNF chromatin remodeling complex, as a negative driver of disease progression. We found that Pbrm1 loss promoted leukemogenesis with significantly shortened latency. Pbrm1-deficient leukemia cells were less immunogenic, and characterized by attenuated interferon signaling and reduced MHC II expression. We explored potential relevance to human leukemia by assessing the involvement of PBRM1 in control of interferon pathway components and found that PBRM1 binds at promoters of a subset of these genes, and most notably at IRF1, which in turn regulates MHC II expression. Our findings revealed a novel role of Pbrm1 in leukemia progression. More generally, CRISPR/Cas9 screening, coupled with phenotypic readouts in vivo, has identified a pathway by which transcriptional control of interferon signaling influences leukemia cell interactions with the immune system.
2023-07-12 | GSE211261 | GEO
Project description:CRISPR/Cas9 screening approaches are powerful tools to identify in vivo cancer dependencies. Hematopoietic malignancies are genetically complex disorders in which sequential acquisition of somatic mutations generates clonal diversity. With time, additional cooperating mutations may drive disease progression. Using an in vivo pooled gene editing screen of epigenetic factors in primary murine hematopoietic stem and progenitor cells (HSPCs), we sought to uncover unrecognized genes that contribute to leukemia progression. We first modeled myeloid leukemia in mice by functionally abrogating both Tet2 and Tet3 in HSPCs followed by transplantation. We then performed pooled CRISPR/Cas9 editing of genes encoding epigenetic factors and identified Pbrm1/Baf180, a subunit of polybromo BRG1/BRM-associated factor (PBAF) SWI/SNF chromatin remodeling complex, as a negative driver of disease progression. We found that Pbrm1 loss promoted leukemogenesis with significantly shortened latency. Pbrm1-deficient leukemia cells were less immunogenic, and characterized by attenuated interferon signaling and reduced MHC II expression. We explored potential relevance to human leukemia by assessing the involvement of PBRM1 in control of interferon pathway components and found that PBRM1 binds at promoters of a subset of these genes, and most notably at IRF1, which in turn regulates MHC II expression. Our findings revealed a novel role of Pbrm1 in leukemia progression. More generally, CRISPR/Cas9 screening, coupled with phenotypic readouts in vivo, has identified a pathway by which transcriptional control of interferon signaling influences leukemia cell interactions with the immune system.
2023-07-12 | GSE211262 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-07-11 | GSE211263 | GEO
Project description:PBRM1 was found to be mutated in a high percentage of clear cell RCCs. We performed knockdown of PBRM1 via siRNA and compared with scrambled control in three different RCC cell lines. PBRM1 siRNA and mock treated cell lines were normalized together with 'hypoxic' clear cell renal tumors and normal renal tissue samples from GSE17818.
2011-01-20 | E-GEOD-22316 | biostudies-arrayexpress
Project description:Polybromo-1 (PBRM1), which encodes a specific subunit of the pBAF chromatin remodeling complex, is inactivated in multiple malignancies including 50% of clear cell renal cell carcinoma. At present, a therapeutic strategy that selectively targets PBRM1 defects does not exist. PBRM1 is involved in multiple cellular processes including transcription, replication and DNA repair. Using high-throughput screens and multiple isogenic and non-isogenic models, we found that PBRM1 defects cause synthetic lethality with several clinical PARP inhibitors, both in vitro and in vivo. This effect was enhanced using combinations with either small molecule ATR or BET inhibitors. Mechanistically, PBRM1 defects caused increased replication stress, R-loop formation and genomic instability that was exacerbated by PARP inhibitors. We also found that PARP and ATR inhibitors activate the cGAS-STING innate immunity pathway in PBRM1-deficient but not in PBRM1-proficient cells. These data provide the pre-clinical rationale for assessing PARP inhibitors as a monotherapy or in combination with ATR inhibitors or immune checkpoint inhibitors, in patients with PBRM1-deficient cancers.
2022-02-21 | PXD017826 | Pride
Project description:While type I interferon (IFN) is best known for its key role against viral infection, accumulating preclinical and clinical data indicate that robust type I IFN production in the tumor microenvironment promotes cancer immunosurveillance and contributes to the efficacy of various antineoplastic agents, notably immunogenic cell death inducers. Here, we report that malignant blasts from patients with acute myeloid leukemia (AML) release type I IFN via a Toll-like receptor (TLR3)-dependent mechanism that is not influenced by treatment. While in these patients the ability of type I IFN to stimulate anticancer immune responses was abolished by immunosuppressive mechanisms driven by malignant blasts, type I IFN turned out to exert direct cytostatic, cytotoxic and chemosensitizing activity in primary AML blasts, leukemic stem cells from AML patients and AML xenograft models. Finally, a genetic signature of type I IFN signaling has independent prognostic value on relapse-free survival and overall survival in cohort of 132 AML patients. These findings delineate a clinically relevant, therapeutically actionable and prognostically informative mechanism through which type I IFN mediates beneficial effects in patients with AML.
2023-03-24 | GSE225138 | GEO