ArticleLeukemia2022
Targeting the NOTCH1-MYC-CD44 axis in leukemia-initiating cells in T-ALL.
Article in Leukemia, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 32 citations in OpenAlex.
- Targeted degradation of protein in hematologic malignancies: mechanisms, therapeutic strategies, and clinical prospects.Cancer gene therapy · 2026Review
- MYC Addiction as a Targetable Vulnerability in Nelarabine-Resistant T-Cell Acute Lymphoblastic Leukemia.Cancer science · 2026Article
- The mitochondria as an emerging target of self-renewal in T-cell acute lymphoblastic leukemia.Cancer biology & therapy · 2025Review
- The ESCRT protein CHMP5 promotes T cell leukemia by enabling BRD4-p300-dependent transcription.Nature communications · 2025Article
- A translational perspective of the malignant hematopoietic proteoglycome.Cell & bioscience · 2025Review
- High CD44 expression and enhanced E-selectin binding identified as biomarkers of chemoresistant leukemic cells in human T-ALL.Leukemia · 2025Article
- Review
- BRD4 Degradation Enhanced Glioma Sensitivity to Temozolomide by Regulating Notch1 via Glu-Modified GSH-Responsive Nanoparticles.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Effects of super-enhancers in cancer metastasis: mechanisms and therapeutic targets.Molecular cancer · 2024Review
- Targeted therapy and immunotherapy for T cell acute lymphoblastic leukemia/lymphoma.Annals of hematology · 2023Review
- A Comprehensive Analysis of the Expression Profiles of KCTD Proteins in Acute Lymphoblastic Leukemia: Evidence of Selective Expression of KCTD1 in T-ALL.Journal of clinical medicine · 2023Article
- DNA polymerase POLD1 promotes proliferation and metastasis of bladder cancer by stabilizing MYC.Nature communications · 2023Article
- Specific lncRNA signatures discriminate childhood acute leukaemias: a pilot study.Cancer cell international · 2022Article
- Targeting Leukemia-Initiating Cells and Leukemic Niches: The Next Therapy Station for T-Cell Acute Lymphoblastic Leukemia?Cancers · 2022Review
- Targeting micro-environmental pathways by PROTACs as a therapeutic strategy.Seminars in cancer biology · 2022Review
Corrections and comments
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Authors and funding
16 authors at 1 institution in 1 country.
Funding
Abstract
The NOTCH1-MYC-CD44 axis integrates cell-intrinsic and extrinsic signaling to ensure the persistence of leukemia-initiating cells (LICs) in T-cell acute lymphoblastic leukemia (T-ALL) but a common pathway to target this circuit is poorly defined. Bromodomain-containing protein 4 (BRD4) is implicated to have a role in the transcriptional regulation of oncogenes MYC and targets downstream of NOTCH1, and here we demonstrate its role in transcriptional regulation of CD44. Hence, targeting BRD4 will dismantle the NOTCH1-MYC-CD44 axis. As a proof of concept, degrading BRD4 with proteolysis targeting chimera (PROTAC) ARV-825, prolonged the survival of mice in Notch1 mutated patient-derived xenograft (PDX) and genetic models (ΔPTEN) of T-ALL. Single-cell proteomics analysis from the PDX model, demonstrated quantitative reduction of LICs (CD34+ CD7+ CD19-) and downregulation of the NOTCH1-MYC-CD44 axis, along with cell cycle, apoptosis and PI3K/Akt pathways. Moreover, secondary transplantation from PDX and ΔPTEN models of T-ALL, confirmed delayed leukemia development and extended survival of mice engrafted with T-ALL from ARV-825 treated mice, providing functional confirmation of depletion of LICs. Hence, BRD4 degradation is a promising LIC-targeting therapy for T-ALL.
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Registered trials
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