Prediction of Venetoclax Activity in Precursor B-ALL by Functional Assessment of Apoptosis Signaling
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PROVIDER: PRJNA510117 | ENA |
REPOSITORIES: ENA
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Project description:Small molecule inhibitors of key apoptosis regulators have been developed that bind to anti-apoptotic molecules like BCL-2, leading to release of pro-apoptotic proteins and cell death induction. This study shows that functional analysis of the interplay of apoptosis regulators in precursor B-ALL predicts preclinical in vivo activity of the BCL-2 inhibitor venetoclax and provides a robust assay for upfront identification of leukemias eligible for therapy.
2019-08-06 | GSE123883 | GEO
Project description:Deregulated cell death pathways contribute to leukemogenesis and treatment failure in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Intrinsic apoptosis signaling is regulated by different proapoptotic and antiapoptotic molecules: proapoptotic BCL-2 homology domain 3 (BH3) proteins activate prodeath molecules leading to cellular death, while antiapoptotic molecules including B-cell lymphoma 2 (BCL-2) prevent activation of prodeath proteins and counter-regulate apoptosis induction. Inhibition of these antiapoptotic regulators has become a promising strategy for anticancer treatment, but variable anticancer activities in different malignancies indicate the need for upfront identification of responsive patients. Here, we investigated the activity of the BCL-2 inhibitor venetoclax (VEN, ABT-199) in B-cell precursor acute lymphoblastic leukemia and found heterogeneous sensitivities in BCP-ALL cell lines and in a series of patient-derived primografts. To identify parameters of sensitivity and resistance, we evaluated genetic aberrations, gene-expression profiles, expression levels of apoptosis regulators, and functional apoptosis parameters analyzed by mitochondrial profiling using recombinant BH3-like peptides. Importantly, ex vivo VEN sensitivity was most accurately associated with functional BCL-2 dependence detected by BH3 profiling. Modeling clinical application of VEN in a preclinical trial in a set of individual ALL primografts, we identified that leukemia-free survival of VEN treated mice was precisely determined by functional BCL-2 dependence. Moreover, the predictive value of ex vivo measured functional BCL-2 dependence for preclinical in vivo VEN response was confirmed in an independent set of primograft ALL including T- and high risk-ALL. Thus, integrative analysis of the apoptosis signaling indicating mitochondrial addiction to BCL-2 accurately predicts antileukemia activity of VEN, robustly identifies VEN-responsive patients, and provides information for stratification and clinical guidance in future clinical applications of VEN in patients with ALL.
| S-EPMC6662703 | biostudies-literature
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
Project description:Despite the transformative impact of venetoclax-azacitidine in treating acute myeloid leukemia (AML), reliable markers for accurately predicting patient responses remain urgently needed. To address this challenge, we employed a multidisciplinary approach that combined transcriptomic profiling, ex vivo drug sensitivity testing, functional assays, and clinical data to identify robust predictors of venetoclax-azacitidine response. We pinpointed a set of core genes linked to both ex vivo and in vivo drug responsiveness, validated through CRISPR-Cas9 screens in the setting of both venetoclax and azacitidine therapies. In particular, silencing BCL2L1 and PINK1 preferentially enhanced response to the venetoclax-azacitidine treatment. Building on these insights, we further developed and validated an 8-gene random forest model (RF8) that demonstrated high specificity and sensitivity in four independent cohorts comprising 498 patients. This model was capable of distilling downstream effects of genetic alterations to assist in predicting treatment response and outperformed existing genetic mutation-based signatures. Furthermore, the RF8 score demonstrated a nearly monotonic relationship with venetoclax-azacitidine response probabilities and patient outcomes, enabling precise stratification of patients. These findings illustrated the feasibility of translating integrated transcriptomic and drug-response profiling data into more refined risk stratification approaches, offering a new avenue for optimizing clinical decision-making in AML.
2025-02-18 | GSE289785 | GEO
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
Project description:Improved Prediction of Venetoclax and Azacitidine Efficacy in Acute Myeloid Leukemia through Machine Learning
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Project description:IMPRINTS-CETSA data acquisition of Kasumi-1 cells treated with Vehicle (DMSO), Venetoclax, Decitabine, Azacitidine and Azacitidine+Venetoclax using TMT 16 plex.
2024-10-23 | PXD056183 | Pride
Project description:IMPRINTS-CETSA data acquisition of Kasumi-1 cells treated with Vehicle (DMSO), Venetoclax, Decitabine, Azacitidine and Azacitidine+Venetoclax using TMT 16 plex.
2024-10-23 | PXD056189 | Pride
Project description:Determinants of venetoclax resistance
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Project description:Determinants of venetoclax resistance
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