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:Wastewater treatment plant effluents (WWTPE) represent a pervasive source of pharmaceutically active compounds in surface waters, with the serotonin and norepinephrine reuptake inhibitor venlafaxine (VEN) frequently detected at elevated concentrations in receiving waters worldwide. VEN is a chiral pharmaceutical administered as a racemic (50:50) mixture of R- and S-enantiomers, which exhibit distinct pharmacological activities and can be selectively degraded or enriched in effluent depending on treatment processes. However, little is known about the stereoselective toxicological effects of VEN in fish. This work investigates the effects of VEN exposure on Etheostoma caeruleum (rainbow darter) using transcriptomic profiling.
2026-03-01 | GSE292719 | GEO
Project description:Venetoclax (ven) combined with the hypomethylating agent azacytidine (aza) is a widely used therapy for Acute Myeloid Leukemia (AML), however, most patients develop resistance. A genome-wide CRISPR screen showed that loss of genes involved in translation conferred sensitivity to ven but not ven+palbo. Accordingly, we show that increased translation occurs after AML cells are challenged with ven, and ven+palbo blocks this increase. We also found that loss of BAX, which leads to ven resistance, was overcome by combination with CDK4/6 inhibitors. Conversely, loss of RB1, a known mechanism of resistance to CDK4/6 inhibitors, was mitigated by ven+palbo. This work suggests that the combination of ven+palbo is a potential novel therapy for AML for potential subpopulations that may benefit the most from this treatment, as well as targeting translation as a means to overcome ven resistance.
2025-11-11 | GSE291338 | GEO
Project description:Despite efficacy of FLT3 and BCL2 inhibition in acute myeloid leukemia (AML), relapse limits survival. Mutation status and AML monocytic differentiation are implicated in resistance. On-treatment tumor evolution may select for genetically distinct clones or shifts in differentiation not resolvable by bulk sequencing. We performed multiomic single cell (SC) DNA/protein and RNA/protein profiling of patients treated on a clinical trial of the BCL2 inhibitor venetoclax and the FLT3 inhibitor gilteritinib (Ven/Git) to characterize immunophenotypic, transcriptional, and genetic clonal evolution on therapy. We found that while Ven/Gilt effectively eliminated FLT3 mutant clones, it selected for RAS mutations, RAS pathway activation and RAS-associated monocytic differentiation. In an in vitro model of monocytic differentiation associated with heightened RAS pathway activation, we demonstrated that MEK inhibition re-sensitized to Ven/Gilt. Kinome profiling of Molm14 cells, both NRAS WT and NRAS G12C, both treatment-naive and venetoclax resistant, additionally shows RAS upregulation with venetoclax resistance. These data indicate RAS signaling is central to FLT3 and BCL2 inhibitor resistance, is tightly coupled to monocytic differentiation and can be overcome by RAS pathway inhibition.
2026-06-15 | PXD068585 | Pride
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:Venetoclax (ven) combined with the hypomethylating agent azacytidine (aza) is a widely used therapy for Acute Myeloid Leukemia (AML), however, most patients develop resistance. Using RNASeq, we identified loss of Ikaros (IKZF1) as a potential resistance mechanism to ven+palbo. Examination of cells with IKZF1-loss revealed upregulation of the receptor, AXL, with concordant AXL inhibitor sensitivity in AML tumors harboring IKZF1 mutations. This work suggests that the combination of ven+palbo is a potential novel therapy for AML for potential subpopulations that may benefit the most from this treatment, as well as targeting translation as a means to overcome ven resistance.
2025-11-11 | GSE291339 | GEO