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TP53-mediated therapy-related clonal hematopoiesis contributes to doxorubicin-induced cardiomyopathy by augmenting a neutrophil-mediated cytotoxic response in a murine model

ABSTRACT: TP53-mediated therapy-related clonal hematopoiesis contributes to doxorubicin-induced cardiomyopathy by augmenting a neutrophil-mediated cytotoxic response in a murine model

PROVIDER: PRJNA727317 | ENA |

REPOSITORIES: ENA

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TP53-mediated therapy-related clonal hematopoiesis contributes to doxorubicin-induced cardiomyopathy by augmenting a neutrophil-mediated cytotoxic response in a murine model

Project description:Therapy-related clonal hematopoiesis (t-CH) is often observed in cancer survivors. This form of clonal hematopoiesis typically involves somatic mutations in driver genes that encode components of the DNA damage response (DDR) and confer hematopoietic stem and progenitor cells (HSPC) with resistance to the genotoxic stress of the cancer therapy. A model of TP53-mediated t-CH was established through the transfer of Trp53-mutant HSPC to mice followed by treatment with a course of the chemotherapeutic agent doxorubicin. These studies revealed that neutrophil infiltration in the heart significantly contributes to doxorubicin-induced cardiac toxicity and that this condition is amplified in the model of Trp53-mediated t-CH. These data suggest t-CH could contribute to the elevated heart failure risk that occurs in cancer survivors.

2021-05-05 | GSE173840 | GEO

TP53-mediated therapy-related clonal hematopoiesis contributes to doxorubicin-induced cardiomyopathy by augmenting a neutrophil-mediated cytotoxic response.

Project description: Not available

| S-EPMC8410064 | biostudies-literature

ATACseq of FHSD iPSC control vs doxorubicin

Project description:FSHD iPSC and TP53 KO FSHD iPSC were treated with vehicle or doxorubicin and then harvested for ATACseq

2021-05-21 | GSE149234 | GEO

Transcription profiling of 5 human parental cell lines and 3 drug resistant variants by culturing the former continuously in the presence of cytotoxic drug doxorubicin

Project description:Title: Analysis of gene expression changes involved in the development of acquired drug resistance.<br> Description: In vitro model of drug resistance consisting of 5 parental cell lines and 3 drug resistant variants by culturing the former continuously in the presence of cytotoxic drug doxorubicin. Model used to identify genes involved in the drug resistant phenotype.

2006-09-01 | E-MIMR-11 | biostudies-arrayexpress

Transcriptional co-activators YAP1-TAZ of Hippo signalling in doxorubicin-induced cardiomyopathy

Project description:Aims: Hippo signalling is an evolutionarily conserved pathway that controls organ size by regulating apoptosis, cell proliferation and stem cell self-renewal. Recently, the pathway has been shown to exert powerful growth regulatory activity in cardiomyocytes. However, the functional role of this stress- and cell death-related pathway in the human heart and cardiomyocytes is not known. In this study, we investigated the role of the transcriptional co-activators of Hippo signalling, YAP and TAZ, in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) in response to cardiotoxic agents and investigated the effects of modulating the pathway on cardiomyocyte function and survival. Methods and Results: RNA sequencing analysis of human heart samples with doxorubicin-induced end-stage heart failure and healthy controls showed YAP and ERBB2 (HER2) as upstream regulators of differentially expressed genes correlated with doxorubicin treatment. Thus, we tested the effects of doxorubicin and/or small molecule inhibitor lapatinib on hiPSC-CM in vitro . Using an automated high contentscreen of 96 clinically relevant chemotherapeutic drugs, we showed that doxorubicin induced the highest activation of YAP/TAZ nuclear translocation in both hiPSC-CM and control MCF7 breast cancer cells. The overexpression of YAP rescued doxorubicin- induced cell loss in hiPSC-CM by inhibiting apoptosis and inducing proliferation. In contrast, silencing of YAP and TAZ by siRNAs resulted in elevated mitochondrial membrane potential loss in response to doxorubicin. Human iPSC-CM calcium transients did not change in response to YAP/TAZ silencing. Conclusions: Our results suggest that Hippo signalling is involved in clinical anthracycline-induced cardiomyopathy. Modelling with hiPSC-CM in vitro showed similar responses to doxorubicin as adult cardiomyocytes and revealed a potential cardioprotective effect of YAP in doxorubicin-induced cardiotoxicity.

2022-01-21 | GSE193861 | GEO

Detoxifying doxorubicin

Project description:Detoxifying doxorubicin

| PRJNA422761 | ENA

SARS-CoV-2 spike sequence dictates host TP53 activity and COVID-19 pathogenicity

Project description:SARS-CoV-2 induces widespread transcriptomic changes in host cells upon infection, in part through activation and modulation of innate immunity pathways and downstream gene regulation. However, the mechanisms by which SARS-CoV-2 and its evolutionary variants differentially affect host cell transcriptomic states remain largely unclear. Through chromatin proteomic (iDAPT-MS) analysis, we found that although SARS-CoV-2 and other pathogenic coronaviruses exhibit similar proteomic shifts on chromatin, SARS-CoV-2 uniquely promotes TP53 nuclear accumulation and activation. Parallel assessment of SARS-CoV-2 viral protein expression on host chromatin states (ATAC-seq) identifies intracellular spike protein as a key determinant of virus-mediated chromatin accessibility changes. Multilevel chromatin profiling reveals increased TP53 nuclear accumulation, TP53-associated chromatin accessibility changes, and TP53 target gene activation upon expression of SARS-CoV-2 alpha (B.1.1.7) and delta (B.1.617.2) spike variants relative to the ancestral spike sequence. TP53, ACE2, and furin cleavage are required for these changes, driving decreased cellular proliferation, increased cellular senescence, and increased cytokine release. Finally, BA.1 but not BA.2, BA.2.12.1, nor BA.4/BA.5 spike expression leads to attenuated TP53 activity and fusogenicity relative to ancestral spike. Our findings implicate spike-mediated host TP53 activation as a “rheostat” of COVID-19 pathogenicity.

2023-09-09 | PXD034648 | Pride

Gene expression profling of human breast carcinoma-associated fibroblasts treated with paclitaxol or doxorubicin at therapeutically relevant doses

Project description:Systemic chemotherapy inflicts cytotoxic injuries on breast carcinoma-associated fibroblasts. We profiled the transcriptomes of human breast carcinoma-associated fibroblasts before and after clinically relevant cytotoxic stimuli induced by chemotheraputic agents. Breast cancer associated fibroblasts (BCAFs) were isolated from the tumor specimen by mechanical dissociation and differential centrifugation. The cells at early passages were treated with paclitaxol or doxorubicin at clinically revealent concentration. Total RNA was extracted from the cells at different time points post-treatment for gene expression profiling.

2010-08-03 | E-GEOD-23399 | biostudies-arrayexpress

Compare proB cells from WT, Tp53-/-, Lnk-/-, Tp53-/-Lnk-/- mice and Tp53-/-Lnk-/-B-ALL

Project description:The adaptor protein LNK (SH2B3) has emerged as an important protein in regulating B cell development B cell leukemia. Loss-of-function mutations in LNK (SH2B3) are found in Philadelphia chromosomeâlike acute lymphoblastic leukemia (Ph-like ALL), but how LNK regulates normal B cell development or promotes leukemogenesis remains unclear. We found that combined loss of Lnk and tumor suppressors Tp53 in mice triggers a highly aggressive and transplantable precursor B-ALL. This study aims to investigate the molecular mechanism by which LNK regulates B-ALL development. We performed expression profiling of bone marrow proB progenitors from WT, Tp53-/-, Lnk-/- and preleukemic healthy Tp53/Lnk double knockout (DKO) mice, as well as leukemic bone marrow cells from DKO mice that have developed B-ALL. Results suggest that Tp53-/-Lnk-/- B-ALLs display similar gene expression profiles to human Ph-like B-ALLs, suggesting this model for preclinical and molecular studies. B220+CD19+CD43+AA4.1+IgM-NK1.1-Ly6c- bone marrow proB cells were double sorted from WT, Tp53-/-, Lnk-/- and preleukemic healthy Tp53/Lnk double knockout (DKO) mice, as well as leukemic bone marrow cells from DKO mice that have developed B-ALL. RNA was isolated using miRNeasy kit from QIAGEN and processed using the NuGEN Pico kit. The microarray analysis was performed at the PENN Molecular Profiling/Genomics Facility using GeneChip Mouse Gene 2.0ST array (Affymetrix).

2016-04-01 | E-GEOD-76940 | biostudies-arrayexpress

Self-maintenance of Cardiac Resident Reparative Macrophages Attenuates Doxorubicin-induced Cardiomyopathy through the SR-A1-c-Myc Axis

Project description:Rationale: Doxorubicin-induced cardiomyopathy (DiCM) is a significant cause of heart failure and mortality in cancer patients, in which macrophage-orchestrated inflammation serves as an essential pathogenic mechanism. However, the specific roles of tissue-resident and monocyte-derived macrophages in DiCM remain poorly understood. Objective: Uncovering the origins, phenotypes, and functions of proliferative cardiac resident macrophages and mechanistic insights into the self-maintenance of cardiac macrophage during DiCM progression. Methods and Results: Mice were administrated with doxorubicin to induce cardiomyopathy. Dynamic changes of resident and monocyte-derived macrophages were examined by lineage tracing, parabiosis, and bone marrow transplantation. We found that the monocyte-derived macrophages primarily exhibited a pro-inflammatory phenotype that dominated the whole DiCM pathological process and impaired cardiac function. In contrast, cardiac resident macrophages were vulnerable to doxorubicin insult. The survived resident macrophages exhibited enhanced proliferation and conferred a reparative role. Global or myeloid specifically ablation of class A1 scavenger receptor (SR-A1) inhibited proliferation of cardiac resident reparative macrophages and therefore exacerbated cardiomyopathy in DiCM mice. Importantly, the detrimental effect of macrophage SR-A1 deficiency was confirmed by transplantation of GFP+ wild type bone marrow. At the mechanistic level, we show that c-Myc, a key transcriptional factor for the SR-A1-P38-SIRT1 pathway, mediated the effect of SR-A1 in reparative macrophage proliferation in DiCM. Conclusions: The SR-A1-c-Myc axis may represent a promising target to treat DiCM through augmentation of cardiac resident reparative macrophage proliferation.

2023-03-31 | GSE147834 | GEO

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