ArticleThe Journal of clinical investigation2019
BETP degradation simultaneously targets acute myelogenous leukemia stem cells and the microenvironment.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
What it found
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The trial behind it
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Who cites it
42 citing papers in PubMed, 71 citations in OpenAlex.
- Targeted degradation of protein in hematologic malignancies: mechanisms, therapeutic strategies, and clinical prospects.Cancer gene therapy · 2026Review
- Article
- Mechanisms and Design Principles of Proteolysis-Targeting Chimeras and Their Emerging Applications.ACS pharmacology & translational science · 2026Review
- TrypPROTACs Unlocking New Therapeutic Strategies for Chagas Disease.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Review
- Advances in the application of patient-derived xenograft models in acute leukemia resistance.Cancer drug resistance (Alhambra, Calif.) · 2025Review
- Divergent Processing of Cell Stress Signals as the Basis of Cancer Progression: Licensing NFκB on Chromatin.International journal of molecular sciences · 2024Review
- The multi-CDK inhibitor dinaciclib reverses bromo- and extra-terminal domain (BET) inhibitor resistance in acute myeloid leukemia via inhibition of Wnt/β-catenin signaling.Experimental hematology & oncology · 2024Article
- CRISPR screening identifies BET and mTOR inhibitor synergy in cholangiocarcinoma through serine glycine one carbon.JCI insight · 2024Article
- Low doses of IFN-γ maintain self-renewal of leukemia stem cells in acute myeloid leukemia.Oncogene · 2023Article
- EnhancedScience advances · 2023Article
- Cytoprotective, Cytotoxic and Cytostatic Roles of Autophagy in Response to BET Inhibitors.International journal of molecular sciences · 2023Review
- Targeting Unc51-like Autophagy Activating Kinase 1 (ULK1) Overcomes Adaptive Drug Resistance in Acute Myelogenous Leukemia.Molecular cancer research : MCR · 2023Article
- Circular RNA PVT1 Regulates Cell Proliferation, Migration, and Apoptosis by Stabilizing c-Myc and Downstream Target CXCR4 Expression in Acute Myeloid LeukemiaTurkish journal of haematology : official journal of Turkish Society of Haematology · 2023Article
- Optimization of PROTAC Ternary Complex Using DNA Encoded Library Approach.ACS chemical biology · 2023Article
- Lethal activity of BRD4 PROTAC degrader QCA570 against bladder cancer cells.Frontiers in chemistry · 2023Article
- ARV-825 Showed Antitumor Activity against BRD4-NUT Fusion Protein by Targeting the BRD4.Journal of oncology · 2023Article
- Design and characterization of PROTAC degraders specific to protein N-terminal methyltransferase 1.European journal of medicinal chemistry · 2022Article
- Targeting micro-environmental pathways by PROTACs as a therapeutic strategy.Seminars in cancer biology · 2022Review
- Cystine uptake inhibition potentiates front-line therapies in acute myeloid leukemia.Leukemia · 2022Article
Corrections and comments
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Authors and funding
17 authors at 3 institutions in 1 country.
Funding
Abstract
Anti-leukemic effect of BET/BRD4 (BETP) protein inhibition has been largely attributed to transcriptional downregulation of cellular anabolic/anti-apoptotic processes but its effect on bone marrow microenvironment, a sanctuary favoring persistence of leukemia stem/progenitor cells, is unexplored. Sustained degradation of BETP with small-molecule BET proteolysis-targeting chimera (PROTAC), ARV-825, resulted in marked downregulation of surface CXCR4 and CD44, key proteins in leukemia-microenvironment interaction, in AML cells. Abrogation of surface CXCR4 expression impaired SDF-1α directed migration and was mediated through transcriptional down-regulation of PIM1 kinase that in turn phosphorylates CXCR4 and facilitates its surface localization. Down-regulation of CD44/CD44v8-10 impaired cystine uptake, lowered intracellular reduced glutathione and increased oxidative stress. More importantly, BETP degradation markedly decreased CD34+CD38-CD90-CD45RA+ leukemic stem cell population and alone or in combination with Cytarabine, prolonged survival in mouse model of human leukemia including AML-PDX. Gene expression profiling and single cell proteomics confirmed down regulation of the gene signatures associated with 'stemness' in AML and Wnt/β-catenin, Myc pathways. Hence, BETP degradation by ARV-825 simultaneously targets cell intrinsic signaling, stromal interactions and metabolism in AML.
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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.