ArticleBritish journal of pharmacology2016
Bcl-2 phosphorylation confers resistance on chronic lymphocytic leukaemia cells to the BH3 mimetics ABT-737, ABT-263 and ABT-199 by impeding direct binding.
Article in British journal of pharmacology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 60 citations in OpenAlex.
- Spectroscopic Signature of Apoptosis Induced by Venetoclax in Philadelphia-Positive Acute Lymphoblastic Leukemia.Analytical chemistry · 2026Article
- Targeting the IKZF1/BCL-2 axis as a novel therapeutic strategy for treating acute T-cell lymphoblastic leukemia.Cancer biology & therapy · 2025Article
- Profiling protein-protein interactions to predict the efficacy of B-cell-lymphoma-2-homology-3 mimetics for acute myeloid leukaemia.Nature biomedical engineering · 2024Article
- Combination of bortezomib and venetoclax targets the pro-survival function of LMP-1 and EBNA-3C of Epstein-Barr virus in spontaneous lymphoblastoid cell lines.PLoS pathogens · 2024Article
- Targeting a Novel G-Quadruplex in theGenes · 2022Article
- Associating drug sensitivity with differentiation status identifies effective combinations for acute myeloid leukemia.Blood advances · 2022Article
- PIK-75 overcomes venetoclax resistanceAmerican journal of cancer research · 2022Article
- Prime, shock and kill: BCL-2 inhibition for HIV cure.Frontiers in immunology · 2022Review
- Mechanisms of venetoclax resistance and solutions.Frontiers in oncology · 2022Review
- Potential Biomarkers for Treatment Response to the BCL-2 Inhibitor Venetoclax: State of the Art and Future Directions.Cancers · 2021Review
- Selective ERBB2 and BCL2 Inhibition Is Synergistic for Mitochondrial-Mediated Apoptosis in MDS and AML Cells.Molecular cancer research : MCR · 2021Article
- Patient-tailored design for selective co-inhibition of leukemic cell subpopulations.Science advances · 2021Article
- Novel Compounds Synergize With Venetoclax to Target KMT2A-Rearranged Pediatric Acute Myeloid Leukemia.Frontiers in pharmacology · 2021Article
- Anti-apoptotic BCL-2 regulation by changes in dynamics of its long unstructured loop.Communications biology · 2020Article
- Targeting BCL-2 in B-cell malignancies and overcoming therapeutic resistance.Cell death & disease · 2020Review
- BDA-366, a putative Bcl-2 BH4 domain antagonist, induces apoptosis independently of Bcl-2 in a variety of cancer cell models.Cell death & disease · 2020Article
- Mitochondrial Genome-Derived circRNA mc-COX2 Functions as an Oncogene in Chronic Lymphocytic Leukemia.Molecular therapy. Nucleic acids · 2020Article
- Systems analysis of phosphorylation-regulated Bcl-2 interactions establishes a model to reconcile the controversy over the significance of Bcl-2 phosphorylation.British journal of pharmacology · 2019Article
- Evaluating venetoclax and its potential in treatment-naïve acute myeloid leukemia.Cancer management and research · 2019Article
- Prediction of Hot Spots at Myeloid Cell Leukemia-1-Inhibitor Interface Using Energy Estimation and Alanine Scanning Mutagenesis.Biochemistry · 2018Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeAlthough the ongoing clinical trials of ABT-263 and ABT-199 in chronic lymphocytic leukaemia (CLL) have indicated that BH3 mimetics hold considerable promise, understanding the mechanism of CLL resistance to BH3 mimetics remains a challenge. EXPERIMENTAL APPROACH: The LD50 values of ABT-737, ABT-263 and ABT-199 in a number of primary CLL cells from 40 patients, were determined. The levels of Bcl-2 family proteins, including phosphorylated Bcl-2 (pBcl-2) and their interactions were measured by immunoblotting and co-immunoprecipitation. In vitro binding assays were performed by isothermal titration calorimetry and ELISA. BH3 profiling in isolated mitochondria was analysed. KEY
resultsThe ratio of (Mcl-1 + pBcl-2) to Bcl-2 expression provided the most significant predictive marker for the cytotoxic potential of ABT-737, ABT-263 and ABT-199 in the panel of CLL samples. Mechanistically, pBcl-2 inhibited the effects of the ABT compounds on the displacement of Bax and Bim from Bcl-2, thereby suppressing mitochondrial apoptosis. The ABT compounds exhibited 100-300-fold lower binding affinity to the glutamic acid, phosphomimetic, mutant of Bcl-2 (T69E, S70E and S87E; EEE-Bcl-2). BH3 peptides exhibited different rank orders of binding affinities to full-length WT-Bcl-2 and full-length EEE-Bcl-2. CONCLUSIONS AND IMPLICATIONS: Our study suggested that a structural alteration in the BH3-binding groove was induced by phosphorylation of Bcl-2. Our data also provided a framework to overcome resistance of CLL cells to the ABT compounds by combining pBcl-2 kinase inhibitors with the ABT compounds.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.