Effect of pharmacological BCL-2 inhibition with venetoclax on T cell homeostasis [RNA-seq]
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PROVIDER: PRJNA929574 | ENA |
REPOSITORIES: ENA
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Project description:Effect of pharmacological BCL-2 inhibition with venetoclax on T cell homeostasis
| PRJNA929527 | ENA
Project description: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.
2023-09-01 | GSE224080 | GEO
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
Project description:Background: The BCL-2 inhibitor venetoclax in combination with a hypomethylating agent is effective against most acute myeloid leukemia (AML) subtypes, but less so against other high-risk myeloid neoplasms. One resistance mechanism to BCL-2 inhibition is increased dependence on alternate BH3-only anti-apoptotic proteins, such as BCL-xL. Navitoclax is a BCL-2/BCL-xL inhibitor that has been previously studied in hematologic malignancies. Patients and methods: We conducted a Phase 1 study of dose-escalated navitoclax added to venetoclax/decitabine for subjects with 1) secondary (s-AML) or therapy-related AML, 2) accelerated- or blast-phase myelofibrosis (AP/BP-MF), 3) myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes with excess blasts, or 4) relapsed/refractory (R/R) MDS with excess blasts. Results:Sixteen subjects were enrolled. Dose-escalation for BP-MF and s-AML was not completed due to discontinued navitoclax supply. Most common grade ≥3 treatment-emergent adverse events included neutropenia (69%), thrombocytopenia (69%), and febrile neutropenia (47%). No clinically significant bleeding was observed. One dose-limiting toxicity of delayed neutrophil recovery occurred. Among 15 evaluable subjects, the overall objective response rate was 60% (9/15). The recommended phase 2 dose was decitabine 20 mg/m2 days 1-5, venetoclax 400 mg/day days 1-14, and navitoclax 50 mg/day days 1-14 for AP-MF, MDS/MPN, and R/R MDS. Correlative studies indicate preserved immature platelet fractions despite on-target reduction of mature platelets, a reduction in disease-associated aberrant monocytes in subjects with monocytic disease, and higher baseline myeloblast dependence on BCL-2 and BCL-xL as predictive of response. Conclusion:Navitoclax added to venetoclax/decitabine is safely tolerable and is active in patients with high-risk myeloid malignancies.
2026-04-20 | GSE312447 | GEO
Project description:This study aimed to investigate the mechanisms underlying venetoclax (VTX) resistance in multiple myeloma (MM) and develop strategies to prevent or overcome resistance. VTX resistant human myeloma cell lines (HMCLs) were established and analyzed using whole exome sequencing (WES), mRNA-sequencing (mRNAseq), and protein expression assays, along with samples from MM patients collected before and after VTX administration. Acquired VTX-resistance in MM was largely associated with BCL-2 family regulation, including upregulation of anti-apoptotic proteins such as MCL-1, BCL-XL, BCL-2 and downregulation of pro-apoptotic members. No BCL-2 mutation was detected in resistant cell lines or relapse patient samples. We also identified upstream signaling pathways involved in BCL-2 family regulation during acquired resistance, such as cytokine, growth factor receptor tyrosine kinase (RTK)-activated signaling, including the PI3K pathway. MCL-1 stability was also investigated through modulation of post-translational modification, but targeting MCL-1 stability via specific inhibitors had limited success in enhancing VTX sensitivity. Co-inhibition of MCL-1, BCL-XL, and upstream PI3K, RTK (FGF, EGF, and IGF1) mediated signaling enhanced VTX sensitivity. Additionally, the inhibition of AURKA and mitochondrial respiration also affected VTX sensitivity in some resistant HMCLs. The findings underscore the importance of personalized approaches to overcome resistance in relapsed patients, suggesting that combining venetoclax with MCL-1 and BCL-XL inhibitors, or targeting upstream regulatory pathways, warrants further investigation to improve patient outcomes and prolong survival in MM.
2025-05-06 | PXD047149 | Pride
Project description:The anti-apoptotic molecule BCL-2 favors the maintenance of the CD4+ T-cell reservoir during Human immunodeficiency virus (HIV) infection. We investigated directly in-vivo whether BCL-2 inhibition using venetoclax at the initiation of antiretroviral therapy (ART) would reduce the size of the viral reservoir. Twenty-four SIVmac239-infected rhesus macaques (RMs) were initiated on ART at day 14 post-infection (p.i.), alone or in combination with either 10-day treatment with venetoclax or venetoclax plus CD8α depletion, and followed up to day 294 p.i. A rapid, statistically significant, and sustained reduction in the intact SIV reservoir was observed in venetoclax-treated RMs in blood and lymph nodes (LNs). This reduction was driven by reduced survival and depletion of CD4+ T-cell subsets that critically contribute to the reservoir. CD4+ T-cells that persisted after venetoclax treatment exhibited elevated per-cell levels of BCL-2, reduced expression of pro-apoptotic molecules such as PUMA, increased expression of additional anti-apoptotic molecules, including BCL-xL, and a partial reduction in apoptotic sensitivity in ex vivo assays. These findings provide mechanistic insights for the venetoclax-induced pro-cell death changes in CD4+ T-cells, support the rationale for extended venetoclax dosing, and suggest that combining BCL-2 inhibition with agents targeting additional anti-apoptotic molecules can enhance clearance of the viral reservoir in HIV cure strategies.
2026-06-28 | GSE301433 | GEO
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
Project description:Acute myeloid leukemia (AML) remains a cancer with dismal prognosis, particularly in high-risk disease patients and those ineligible for allogeneic stem cell transplantation. BCL-2 inhibitor venetoclax, in combination with hypomethylating agents, has emerged as an effective therapy and forms the backbone of multiple combination therapies in clinical trials. However, venetoclax-based therapy is rarely curative. While multiple venetoclax resistance mechanisms have been discovered, most of these have been identified using cell line models that only partially reflect the heterogeneous composition of human AML. Using paired single-cell data from 8 AML patients with pre- and post-venetoclax therapy samples, we aimed to characterize mechanisms driving venetoclax resistance in a clinically relevant setting.
2025-12-31 | E-MTAB-14143 | biostudies-arrayexpress
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. 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.
2023-07-31 | GSE237923 | GEO
Project description:Dual BCL-xL and BCL-2 Inhibition for Advanced Myeloid Neoplasms: A phase 1 dose-escalation study of Navitoclax, Venetoclax, and Decitabine
| PRJNA1373333 | ENA