Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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. Notably, we identify a distinct CD161low CD218b+ NK cell subpopulation exhibiting the most pronounced proportional increase and transcriptomic changes upon venetoclax treatment.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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE237923 | GEO | 2023/07/31

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

CRISPR Screen of Venetoclax Response-Associated Genes Identifies Transcription Factor ZNF740 as a Key Functional Regulator [RNA-Seq]

Project description:BCL-2 inhibitors such as venetoclax offer therapeutic promise in acute myeloid leukemia (AML) and other cancers, but drug resistance poses a significant challenge. It is crucial to understand the mechanisms that regulate venetoclax response. While correlative studies have identified numerous genes linked to venetoclax sensitivity, their direct impact on the drug response remains unclear. In this study, we targeted around 1,400 genes upregulated in venetoclax-sensitive primary AML samples and carried out a CRISPR knockout screen to evaluate their direct effects on venetoclax response. Our screen identified the transcription factor ZNF740 as a critical regulator, with its expression consistently predicting venetoclax sensitivity across subtypes of the FAB classification. ZNF740 depletion leads to increased resistance to venetoclax, while its overexpression enhances sensitivity to the drug. Mechanistically, our integrative transcriptomic and genomic analysis identifies NOXA as a direct target of ZNF740, which negatively regulates MCL-1 protein stability. Loss of ZNF740 downregulates NOXA and increases the steady state protein levels of MCL-1 in AML cells. Restoring NOXA expression in ZNF740-depleted cells re-sensitizes AML cells to venetoclax treatment. Furthermore, we demonstrated that dual targeting of MCL-1 and BCL-2 effectively treats ZNF740-deficient AML in vivo. Together, our work systematically elucidates the causal relationship between venetoclax response signature genes and establishes ZNF740 as a novel transcription factor regulating venetoclax sensitivity.

2024-09-04 | GSE267342 | GEO

CRISPR Screen of Venetoclax Response-Associated Genes Identifies Transcription Factor ZNF740 as a Key Functional Regulator [CUT&Run]

2024-09-04 | GSE267343 | GEO

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

Anti-leukemic effect of TGN-1062, a novel CDK7 inhibitor, on AML-leukemic stem cells by targeting RNA modification and Mitochondrial metabolism

Project description:High expression of CDK7, a cell cycle regulator and transcriptional modulator, correlates with poor outcomes in acute myeloid leukemia (AML). We report that TGN-1062, a novel CDK7 inhibitor, exhibits significant antileukemic effects by inhibiting cell growth and inducing apoptosis in AML cell lines and primary CD34+CD38- blasts (enriched for leukemia stem cells; LSCs), while sparing normal CD34+CD38- cells (enriched for hematopoietic stem cells; HSCs). Our study revealed that TGN-1062 treatment in primary CD34+CD38- AML blasts suppress RNA m6A modification by downregulating METTL3/14 proteins, key components of the m6A methyltransferase complex that regulate RNA stability and translation. Decrease in METTL proteins reduced BCL-2 m6A RNA modification and led to increased BCL-2 mRNA decay and protein levels. BCL-2 downregulation resulted in disruption of mitochondrial metabolism and mitofusion in LSCs through decrease of HMGB1/HSPB1 and NRF2/DRP1 signaling, respectively. In vivo, TGN-1062 significantly reduced leukemia burden and prolonged survival in a murine MllPTD/WT/Flt3ITD/ITD AML model and in FLT3-WT and inv(16) AML patient-derived xenografts (PDXs). Increased survival in secondary transplant experiments supported TGN-1062 activity on LSCs. Of note, we proved that TGN-1062 synergized with the BCL-2 inhibitor, venetoclax in eliminating LSCs in both murine and PDX AML models, underscoring its potential as a promising therapeutic approach for AML patients.

2024-11-24 | GSE282364 | GEO

M16-106 adult and pediatric ALL clinical trial - RNAseq dataset

Project description:Combining venetoclax, a selective BCL-2 inhibitor, with low-dose navitoclax, a BCL-XL/BCL-2 inhibitor, may potentiate therapeutic BCL-2 and BCL XL inhibition without dose-limiting thrombocytopenia associated with navitoclax monotherapy. The safety and preliminary efficacy of venetoclax with low-dose navitoclax and chemotherapy was assessed in this phase 1 dose escalation study (NCT03181126) in pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia or lymphoblastic lymphoma. Forty-seven patients received treatment. A recommended phase 2 dose of 50 mg navitoclax for adults and 25 mg for patients <45 kg with 400 mg adult-equivalent venetoclax was identified. Delayed hematopoietic recovery was the primary safety finding. The complete remission rate was 60%, including responses in patients who had previously received hematopoietic cell transplantation or immunotherapy. Thirteen (28%) patients proceeded to transplantation or CAR T-cell therapy on study. Venetoclax with navitoclax and chemotherapy was well tolerated and had promising efficacy in this heavily pretreated patient population.

2021-02-17 | GSE162894 | GEO

Project description:Unleashed NK-cell mediated cytotoxicity against AML

| PRJNA1077715 | ENA

Developing enhanced immunotherapy using NKG2A knockout human pluripotent stem cell-derived NK cells

Project description:Cancer immunotherapy is gaining increasing attention. However, immune checkpoints are exploited by cancer cells to evade anti-tumor immunotherapy. Here, we knocked out NKG2A, an immune checkpoint expressed on natural killer (NK) cells, in human pluripotent stem cells (hPSCs) and differentiated these hPSCs into NK (PSC-NK) cells. We show that NKG2A knockout (KO) enhances the anti-tumor and anti-viral capabilities of PSC-NK cells. NKG2A KO endows PSC-NK cells with higher cytotoxicity against HLA-E-expressing glioblastoma (GBM) cells, leukemia cells, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected cells in vitro. The NKG2A KO PSC-NK cells also exerted potent anti-tumor activity in vivo, leading to substantially suppressed tumor progression and prolonged survival of tumor-bearing mice in a xenograft GBM mouse model. These findings underscore the potential of PSC-NK cells with immune checkpoint KO as a promising cell-based immunotherapy. The unlimited supply and ease of genetic engineering of hPSCs makes genetically engineered PSC-NK an attractive option for easily accessible "off-the-shelf" cancer immunotherapy.

2024-10-18 | GSE241039 | GEO

SETDB1 suppresses interferon responses and NK cell-mediated immunosurveillance specifically in monocytic AML: Gene expression profiles of cSAM leukemia cells with Setdb1 depletion [RNA-seq]

Project description:Monocytic acute myeloid leukemia (AML) responds poorly to current treatments, including venetoclax-based therapy. We conducted in vivo and in vitro CRISPR/Cas9 library screenings using a mouse monocytic AML model, and identified SETDB1 and its binding partners (ATF7IP and TRIM33) as crucial tumor promoters in vivo. The growth-inhibitory effect of Setdb1 depletion in vivo was mainly dependent on NK cell-mediated cytotoxicity. Mechanistically, SETDB1 depletion upregulated interferon-stimulated genes and NKG2D ligands through demethylation of histone H3 Lys9 at the monocyte-specific enhancer regions, thereby enhancing their immunogenicity to NK cells and intrinsic apoptosis. Importantly, these effects were not observed in non-monocytic leukemia cells. We also identified the expression of MNDA and its murine counterpart Ifi203 as biomarkers to predict the sensitivity of each AML to SETDB1 depletion. Our study highlights the critical and selective role of SETDB1 in monocytic AML and underscores its potential as a therapeutic target for current unmet needs.

2024-08-03 | GSE266097 | GEO