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Effect of pharmacological BCL-2 inhibition with venetoclax on T cell homeostasis

ABSTRACT: Venetoclax, a BCL-2 specific inhibitor, has been show to confer transcriptional changes in T cell populations. In order to elucidate how these changes may be occuring, we sought to investigate whether there are epigenetic alterations that may offer a potential explanation. To begin to answer this question, we conducted ATAC-sequencing on Treg cells isolated from FOXP3-IRES-GFP mice treated for 14 days with 50mg/kg of venetoclax and assessed for global accessibility changes.

ORGANISM(S): Mus musculus

PROVIDER: GSE224080 | GEO | 2023/09/01

REPOSITORIES: GEO

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Effect of pharmacological BCL-2 inhibition with venetoclax on T cell homeostasis [RNA-seq]

Project description:Venetoclax, a BCL-2 inhibitor, is being increasingly used in the clinic as a single agent or in combination. Thus far, there has been little to show how this drug affects the immune system. Research has been done to characterize the mechanisms of resistance of cancer cells to venetoclax, however, an immune subset of T cells called regulatory T cells has also shown resistence to apoptotic cell death via venetoclax administration. To investigate the effects of venetoclax on the transcriptional landscape of regulatory T cells (with some comparison to conventional T cells), we treated FOXP3-IRES-GFP mice for 14 days with 50mg/kg of venetoclax and analyzed their RNA profiles. We observed that Treg cells upregulate genes involved in Th17 effector cell differentiation, which was not observed in the Tcon counterparts.

2023-09-01 | GSE224092 | GEO

Single-cell transcriptome analysis of human natural killer cells derived from umbilical cord blood in response to the BCL-2 inhibitor venetoclax

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2023-07-31 | GSE237923 | GEO

Transcriptional changes in human natural killer cells derived from umbilical cord blood in response to the BCL-2 inhibitor Venetoclax

Project description:Natural killer (NK) cell-based immunotherapy holds promise for cancer treatment, but its efficacy is still limited, necessitating the development of new strategies. Here, we report an unexpected discovery that venetoclax, the first FDA-approved BCL-2 inhibitor, acts as an immunometabolic modulator to potentiate adoptive NK cell immunotherapy against acute myeloid leukemia (AML). Venetoclax directly activates human NK cells, boosting their cytotoxicity against AML both in vitro and in vivo, independent of BCL-2 inhibition. Venetoclax enhances NK cell binding avidity and lytic granule polarization during immunological synapse (IS) formation.Furthermore, venetoclax promotes mitochondrial respiration and ATP synthesis via the NF-κB pathway, facilitating IS formation and effector function in human NK cells.Our findings establish venetoclax as a multifaceted immunometabolic modulator that enhances NK cell function, providing new insights for augmenting NK cell-mediated cytotoxicity in cancer immunotherapy.

2023-07-31 | GSE237922 | GEO

Effect of venetoclax, tedizolid, and combination treatment on gene expression in a venetoclax-resistant AML cell line

Project description:The goal of this study was to profile the changes in gene expression in an AML cell line with acquired resistance to venetoclax in response to treatment with venetoclax, tedizolid, or combination of the 2 drugs.

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The BCL-2 Inhibitor Venetoclax in Combination with Azacitidine Disrupts Energy Metabolism and Targets Leukemia Stem Cells in Acute Myeloid Leukemia Patients

Project description:The manuscript summarizes clinical and laboratory-based evaluation of 33 AML patients treated with a novel drug combination, venetoclax and azacytidine. Our findings indicate that this regimen is exceptionally promising for the treatment of de novo AML patients. The improvement in outcomes in comparison to conventional therapy is quite remarkable. The manuscript explores the mechanistic basis for the clinical outcomes, testing the hypothesis that venetoclax and azacytidine effectively target leukemia stem cells (LSCs) in vivo. Our findings indicate the regimen is highly active towards the LSC population. Specifically, we describe a mechanism that suppresses the activity of electron transport complex II, resulting in inhibition of oxidative phosphorylation.

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Determinants of venetoclax resistance

Project description:Determinants of venetoclax resistance

| PRJNA558092 | ENA

Determinants of venetoclax resistance

Project description:Determinants of venetoclax resistance

| PRJNA558091 | ENA

Targeting mitochondrial structure sensitizes AML to Venetoclax

Project description:The BCL-2 family plays important roles in acute myeloid leukemia (AML) and Venetoclax, a selective BCL-2 inhibitor, has received FDA approval for treatment of AML. However, drug resistance ensues after prolonged treatment, highlighting the need for a greater understanding of the underlying mechanisms. Using a genome-wide CRISPR/Cas9 screen in human AML, we identified genes whose inactivation sensitizes AML blasts to Venetoclax. Genes involved in mitochondrial organization and function were significantly depleted throughout our screen, including the mitochondrial chaperonin CLPB. We demonstrated that CLPB is upregulated in human AML, it is further induced upon acquisition of Venetoclax resistance and its ablation sensitizes AML cells to Venetoclax. Mechanistically, CLPB maintains the mitochondrial cristae structure via its interaction with the cristae-shaping protein OPA1, whereas its loss promotes apoptosis by inducing cristae remodeling and mitochondrial stress responses. Overall, our data suggest that targeting mitochondrial architecture may provide a promising approach to circumvent Venetoclax resistance.

2019-05-03 | GSE125403 | GEO

Hypomethylating agents sensitize diffuse large B-cell lymphoma to venetoclax

Project description:We established acquired venetoclax resistant OCI-LY1R cell line by treating venetoclax sensitive parental OCI-Ly1 cell line with increasing doses of venetoclax up till 1µM. Parental OCI-Ly1 and venetoiclax-resistant OCI-Ly1R cells were treated with vehicle control or decitabine at 1uM for 3 days. We found that decitabine differantially regulated gene expression in venetoclax sensitive and resistant cells. With gene set enrichment analysis, we identified two pathways that were deregulated by decitabine in both cell lines.

2023-07-25 | GSE223598 | GEO

A novel covalent inhibitor of CDK7 synergizes with Venetoclax in acute myeloid leukemia

Project description:To assess the synergistic effects of CDK7 inhibitor with Venetoclax, we performed RNA sequencing and gene set enrichment analysis using Venetoclax sensitive and resistant model systems. RNA-sequencing from paired Venetoclax-sensitive and Venetoclax-resistant cells treated with CDK7 inhibitor showed downregulation of genes involved in proliferation and apoptosis. CDK7 inhibitor induces apoptosis in AML cells and combined treatment with Venetoclax led to synergistic effects in overcoming resistance.

2023-07-24 | GSE231745 | GEO

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