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A non-canonical R-loop resolving function of PIWIL4 maintains the genomic integrity and leukemic growth of AML cells

ABSTRACT: PIWIL4 enzyme is required for resolving R-loops and for growth of AML cells. We examine the impact of PIWIL4 knockdown and R-loop accumulation on gene expression in AML cell line THP-1

ORGANISM(S): Homo sapiens

PROVIDER: GSE188490 | GEO | 2023/05/28

REPOSITORIES: GEO

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A non-canonical R-loop resolving function of PIWIL4 maintains the genomic integrity and leukemic growth of AML cells [PAR-CLIP]

Project description:PIWIL4 is a RNA binding enzyme required for the resolution of R-loops in AML cells. We examine the RNA associated with PIWIL4 protein in AML cell line THP-1

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Cytoplasmic NPM1 maintains the leukemic state through HOX expression [ChIP-seq] 

Project description:NPM1 is the most frequently mutated gene in cytogenetically normal acute myeloid leukemia (AML). In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c). NPM1 mutations are founding genetic lesions, however it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in downregulation of homeobox (HOX) genes, and differentiation and cell growth arrest of AML cells. Additionally, we show that HOX downregulation is the earliest transcriptional event following the loss of NPM1c from the cytoplasm, preceding and promoting differentiation. Finally, we show that XPO1 inhibition efficiently relocalizes NPM1c to the nucleus, enables differentiation and prolongs survival of Npm1c+ leukemic mice. We describe an exquisite dependency of NPM1-mutant AML cells on NPM1c, providing the rationale for the use of nuclear export inhibitors in AML with mutated NPM1.

2018-08-06 | GSE111179 | GEO

Cytoplasmic NPM1 maintains the leukemic state through HOX expression [RNA-seq]  

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Canonical NF-κB signaling maintains corneal epithelial integrity and prevents corneal aging via retinoic acid.

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Generation of resolving neutrophils with 4-PBA or genetic deletion of TRAM

Project description:We have generated resolving neutrophils with anti-inflammatory potency, through applying the pharmacological agent 4-PBA or genetically depleting TRAM molecule. WT murine neutrophils treated with PBS or 4-PBA for overnight were harvested for scRNAseq analysis to examine the generated resolving neutrophil phenotype. In addtion, we have cultured WT and TRAM KO neutrophils and compared the resolving phenotype via scRNAseq analysis.

2022-04-20 | GSE182356 | GEO

Specialized Pro-resolving Mediators Regulate Treg Differentiation

Project description:We aim to demonstrate a central role for omega-3 derived autacoids, termed specialized pro-resolving mediators (SPM), in the differentiation and maturation of Tregs.

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Transcription termination maintains chromosome integrity.

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Study of human macrophage reprogramming toward a pro-resolving profile by efferocytosis

Project description:Inﬂammation is a physiopathological process triggered by infection or tissue damage. Immune system initiates coordinated sequential steps in response to these danger signals. Once the threat has been contained inflammation has to be subsequently shut down. Inflammation resolution is initiated by the reprogramming of pro-inflammatory macrophages toward a pro-resolving profile. This reprogramming is induced in particular by the non-phlogistic engulfment of apoptotic cells, mostly apoptotic neutrophils, a process called efferocytosis. As a matter of fact, macrophages are an essential linchpin regulating both inflammation triggering and sustaining and inflammation resolution. This duality can be achieved through the tremendous plasticity of these innate immune cells. Indeed, depending on microenvironmental signals (cytokines, efferocytosis, growth factors…) macrophages can adopt numerous diverse and sometimes antagonistic phenotypes. The mechanisms governing these transitions remain relatively scattered especially in human. With this project we propose to explore the mechanisms involved in human macrophage reprogramming toward a pro-resolving profile after efferocytosis. The stakes are high due to the estimated prevalence of chronic inflammatory diseases in Western society is 5 to 7%. Chronic inflammation is a burden to patient due to life-long debilitating illness and increased mortality and is also a burden to society due to high costs for therapy and care. Finding new therapies to limit chronic inflammation establishment and persistence is thus a highly valuable goal.

2021-12-01 | E-MTAB-8885 | biostudies-arrayexpress

Specialized Pro-resolving Mediators Regulate Treg Differentiation

Project description:Specialized Pro-resolving Mediators Regulate Treg Differentiation

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Kynurenine engages Serotonin Receptor 1b in osteoblasts to reinforce Acute Myeloid Leukemia

Project description:We performed RNAseq analysis of primary human osteoblasts co-cultured with the human THP-1 AML cell-line and, in parallel, RNAseq analysis on the THP-1 AML cells exposed to the human primary osteoblasts.

2020-07-15 | GSE154374 | GEO

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