ArticleClinical cancer research : an official journal of the American Association for Cancer Research2016
Binding of Released Bim to Mcl-1 is a Mechanism of Intrinsic Resistance to ABT-199 which can be Overcome by Combination with Daunorubicin or Cytarabine in AML Cells.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05628623 (Eradicating Measurable Residual Disease in Patients With Acute Myeloid Leukemia), which is not on this map. Cited by 151 papers, 1 of them a synthesis that pooled it.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Eradicating Measurable Residual Disease in Patients With Acute Myeloid Leukemia (AML) Prior to StEm Cell Transplantation (ERASE): A MyeloMATCH Treatment Trial
Who cites it
151 citing papers in PubMed, 1 synthesis or guideline pooled it, 248 citations in OpenAlex.
- Venetoclax combined with hypomethylating agents or low-dose cytarabine as induction chemotherapy for patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy: a systematic review and meta-analysis.Clinical and experimental medicine · 2023Pooled it
- Trial
- Venetoclax Combined With Low-Dose Cytarabine for Previously Untreated Patients With Acute Myeloid Leukemia: Results From a Phase Ib/II Study.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2019Trial
- TP53 mutations drive therapy resistance through post-mitochondrial caspase blockade.Cell death & disease · 2026Article
- Article
- Design, Synthesis, and Biological Evaluation of Selective CDK4/9 Inhibitors.ACS medicinal chemistry letters · 2026Article
- Impact of venetoclax trough levels on safety and efficacy in the treatment of acute myeloid leukemia.Scientific reports · 2026Article
- Inhibition of CDK9 enhances AML cell death induced by combined venetoclax and azacitidine.Molecular oncology · 2026Article
- Enhancing the Nucleoside Analog Response with Translational Therapeutic Approaches to Overcome Resistance.Cells · 2026Review
- Phenazine 5,10-dioxide analogues as potential therapeutics in AML: Efficacy on patient-derived blasts, in zebrafish larvae xenografts and synergy with venetoclax.Translational oncology · 2026Article
- Article
- NaCells · 2025Article
- Apoptosis-targeting BH3 mimetics: transforming treatment for patients with acute myeloid leukaemia.Nature reviews. Clinical oncology · 2025Review
- Superoxide-mediated phosphorylation and stabilization of Mcl-1 by AKT underlie venetoclax resistance in hematologic malignancies.Leukemia · 2025Article
- Current Therapeutic Strategies for FLT3-Mutated Acute Myeloid Leukemia: A Narrative Review.Cureus · 2025Review
- Article
- MCL1 may not mediate chemoresistance.bioRxiv : the preprint server for biology · 2025Article
- SIRT5 inhibition impairs mitochondrial metabolism and enhances venetoclax-induced elimination of acute myeloid leukemia cells.Leukemia · 2025Article
- Unraveling Venetoclax Resistance: Navigating the Future of HMA/Venetoclax-Refractory AML in the Molecular Era.Cancers · 2025Review
- A combination of Dihydroartemisinin and Venetoclax enhances antitumor effect in AML via C-MYC/BCL-XL/MCL-1 triple targeting.Discover oncology · 2025Article
91 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
14 authors at 4 institutions in 3 countries.
Funding
Abstract
purposeTo investigate the molecular mechanism underlying intrinsic resistance to ABT-199. EXPERIMENTAL
designWestern blots and real-time RT-PCR were used to determine levels of Mcl-1 after ABT-199 treatment alone or in combination with cytarabine or daunorubicin. Immunoprecipitation of Bim and Mcl-1 were used to determine the effect of ABT-199 treatment on their interactions with Bcl-2 family members. Lentiviral short hairpin RNA knockdown of Bim and CRISPR knockdown of Mcl-1 were used to confirm their role in resistance to ABT-199. JC-1 assays and flow cytometry were used to determine drug-induced apoptosis.
resultsImmunoprecipitation of Bim from ABT-199-treated cell lines and a primary patient sample demonstrated decreased association with Bcl-2, but increased association with Mcl-1 without corresponding change in mitochondrial outer membrane potential. ABT-199 treatment resulted in increased levels of Mcl-1 protein, unchanged or decreased Mcl-1 transcript levels, and increased Mcl-1 protein half-life, suggesting that the association with Bim plays a role in stabilizing Mcl-1 protein. Combining conventional chemotherapeutic agent cytarabine or daunorubicin with ABT-199 resulted in increased DNA damage along with decreased Mcl-1 protein levels, compared with ABT-199 alone, and synergistic induction of cell death in both AML cell lines and primary patient samples obtained from AML patients at diagnosis.
conclusionsOur results demonstrate that sequestration of Bim by Mcl-1 is a mechanism of intrinsic ABT-199 resistance and supports the clinical development of ABT-199 in combination with cytarabine or daunorubicin for the treatment of AML. Clin Cancer Res; 22(17); 4440-51. ©2016 AACR.
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Registered trials
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.