123a4565-16f6-4c41-8bec-fe7c2667b572 - samples
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ABSTRACT:
PROVIDER: EGAD00001008365 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:Single-cell Long read data of a cohort of CLL patients receiving Venetoclax treatment for VEN resistance study.
| EGAD00001008367 | EGA
Project description:CITEseq data of CLL patients receiving VEN treatment for resistance study
| EGAD00001008366 | EGA
Project description:Deep single-cell multi-omic profiling of drug resistance in patients with relapsed or refractory (rr) acute myeloid leukemia (AML) is a promising approach to understand and identify the molecular and cellular determinants of drug resistance. Here, we address this challenge by integrating single-cell ex vivo drug profiling (pharmacoscopy) with both bulk and single-cell resolved DNA, RNA, and protein profiling, as well as clinical annotations across samples of a cohort of 21 rrAML patients. Unsupervised data integration revealed ex vivo response to the Bcl-2 inhibitor venetoclax (VEN) to be significantly reduced in patients treated with the combination of a hypomethylating agent (HMA) and VEN compared to patients pre-exposed to HMA only, while also exposing innate Ven resistance in a subset of VEN-naive patients. Systematic molecular integration retrieved known and novel molecular mechanisms underlying VEN resistance and identified alternative therapeutic strategies in VEN resistant samples, including targeting increased proliferation by PLK inhibitor volasertib. Across data modalities, high CD36 expression on AML blasts was associated with VENres, while CD36-targeted antibody treatment ex vivo revealed striking sensitivity in VEN resistant AML. In summary, we showcase how single-cell multi-omic and functional profiling can facilitate the discovery of drug resistance mechanisms and emergent treatment vulnerabilities. Our dataset represents a comprehensive molecular and functional profiling of rrAML at single-cell resolution, providing a valuable resource for future studies.
| MSV000092970 | MassIVE
Project description:Single-cell RNA-sequencing and other genome-wide approaches were applied to a cohort of CLL patients receiving Venetoclax treatment to study mechanisms of resistance.
| EGAS00001005815 | EGA
Project description:B-cell receptor (BCR) signaling is a central driver in chronic lymphocytic leukemia (CLL), along with activation of pro-survival pathways (e.g., NF- κB) and aberrant anti-apoptotic (e.g., BCL2), culminating to CLL cell survival and drug-resistance. Front-line targeted therapies such as ibrutinib (IBR) and venetoclax (VEN) have radically improved CLL management. Yet, persisting CLL cells lead to relapse in ~20% of patients, signifying the need for alternative therapeutics with novel approaches to CLL cell elimination and overcoming resistance mechanisms. SpiD3 is a novel spirocyclic dimer of analog 19 displaying NF-κB inhibitory activity. Recently, we have shown that SpiD3 inhibits CLL proliferation and induces cytotoxicity, by promoting futile activation of the unfolded response pathway (UPR) and generation of reactive oxygen species (ROS), resulting in insurmountable endoplasmic reticulum stress. RNA-sequencing analysis of IBR- and VEN-resistant CLL cell lines revealed ferroptosis, UPR signaling, and oxidative stress among the top pathways modulated by SpiD3 treatment. By examining SpiD3 induced protein aggregation, ROS production, and ferroptosis in preclinical models of CLL, our data demonstrates marked SpiD3-induced anti-leukemic properties and CLL cell cytotoxicity, including in cell lines resistant to current front-line therapeutics, substantiating the development of SpiD3 as a novel therapeutic approach to management of relapse/refractory CLL disease.
2024-08-30 | GSE267095 | GEO
Project description:Bruton's tyrosine kinase (BTK) inhibitors are effective treatments for chronic lymphocytic leukemia (CLL) due to BTK’s role in B-cell survival and proliferation. Though effective, resistance occurs most commonly due to a BTKC481S mutation that inhibits drug binding. Here, we sought to understand the impact of co-occurring BTK resistance mutations with known CLL driver mutations and the differential transcriptomic behavior of BTK-resistant CLL subclones in six patients who acquired BTKC481S mutations. We utilize MAS-seq, a long-read scRNAseq technology, to increase transcript coverage and expand the set of mutations that can be used to link cells to tumor subclones.
2024-03-01 | GSE259253 | GEO
Project description:Therapy resistance represents a major clinical challenge in acute myeloid leukemia (AML). Here we define a “MitoScore” signature that identifies high mitochondrial oxidative phosphorylation (OxPHOS) in vivo and in AML patients. Primary AML cells with cytarabine (AraC) resistance and high MitoScore relied on mitochondrial Bcl2 and were highly sensitive to venetoclax (VEN) plus AraC (but not to VEN plus azacytidine, AZA). Single-cell transcriptomics of VEN+AraC-residual cell populations revealed adaptive resistance associated with changes in OxPHOS, electron transport chain complex (ETC) and the TP53 pathway.
2021-11-12 | GSE183329 | GEO
Project description:Deregulated apoptosis signaling is characteristic for many cancers and contributes to leukemogenesis and treatment failure in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Apoptosis is controlled by different pro- and anti-apoptotic molecules. Inhibition of anti-apoptotic molecules like B-cell lymphoma 2 (BCL-2) has been developed as therapeutic strategy. Venetoclax (VEN), a selective BCL-2 inhibitor has shown clinical activity in different lymphoid malignancies and is currently evaluated in first clinical trials in BCP-ALL. However, insensitivity to VEN has been described constituting a major clinical concern. Here, we addressed and modeled VEN-resistance in BCP-ALL, investigated the underlying mechanisms in cell lines and patient-derived xenograft (PDX) samples and identified potential strategies to overcome VEN-insensitivity. Leukemia lines with VEN-specific resistance were generated in vitro and further characterized using RNA-seq analysis. Interestingly, gene sets annotated to the citric/tricarboxylic acid cycle and the respiratory electron transport chain were significantly enriched and upregulated, indicating increased mitochondrial metabolism in VEN-resistant ALL. Metabolic profiling showed sustained high mitochondrial metabolism in VEN-resistant lines as compared to control lines. Adccordingly, primary PDX-ALL samples with intrinsic VEN-insensitivity showed higher oxygen consumption and ATP production rates, further highlighting that increased mitochondrial activity is a characteristic feature of VEN-resistant ALL. VEN-resistant PDX-ALL showed significant higher mitochondrial DNA content and differed in mitochondria morphology with significantly larger and elongated structures, further corroborating our finding of augmented mitochondrial metabolism upon VEN-resistance. Using oligomycin, an inhibitor of the complex V/ATPase subunit, we found synergistic activity and apoptosis induction in VEN-resistant BCP-ALL cell lines and PDX samples, demonstrating that acquired and intrinsic VEN-insensitivity can be overcome by co-targeting BCL-2 and the OxPhos pathway. These findings of reprogrammed, high mitochondrial metabolism in VEN-resistance and synergistic activity upon co-targeting BCL-2 and oxidative phosphorylation, strongly suggest further preclinical and potential clinical evaluation in VEN-resistant BCP-ALL.
2024-07-04 | GSE245284 | GEO
Project description:Acute myeloid leukemia (AML) is a hematopoietic cancer characterized by the proliferation and accumulation of aberrant immature myeloid progenitor blasts in bone marrow and peripheral blood. Venetoclax (VEN), a selective B-cell lymphoma 2 (BCL-2) inhibitor, has received FDA approval for AML treatment in combination with hypomethylating agents (HMA). However, treatment failure and therapy resistance present an urgent need for new therapies to overcome VEN resistance and enhance VEN efficacy. We propose inhibition of SUMOylation as a novel therapy with the potential to address this need. SUMOylation regulates protein function by covalently attaching Small Ubiquitin-like MOdifier (SUMO) proteins to target proteins via an enzymatic cascade. Our study aims to evaluate the effects of SUMOylation inhibition on anti-AML activity of VEN and dissert the underlying mechanism.
2024-05-27 | GSE267885 | GEO
Project description:Venetoclax (VEN) has transformed the therapy of acute myeloid leukemia (AML), but resistance and relapse are a major challenge. Monocytic differentiation was proposed as a cause of VEN resistance, but clinical and laboratory evidence is conflicting. Here we harness AML patientderived induced pluripotent stem cells (iPSCs) and Genotyping of Transcriptomes (GoT) to interrogate how mutational status and differentiation stage affect VEN sensitivity independently of one another. Findings in primary and iPSC-derived AML stem cells (LSCs) and monocytic blasts, together with clinical trial data, reveal that monocytic blasts are resistant to VEN, in contrast to LSCs, which express high levels of BCL2 and are sensitive, and that it is the latter, but not the former, that determines the clinical outcome. Crucially, N/KRAS-mutant LSCs produce more monocytic blasts, downregulate BCL2 and are resistant to VEN, driving clinical resistance or relapse. We thus provide a unifying mechanistic model of VEN resistance in AML.
2024-08-09 | GSE235206 | GEO