ArticleNature medicine2009
Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia.
Article in Nature medicine, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 248 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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.
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Who cites it
248 citing papers in PubMed, 438 citations in OpenAlex.
- NOTCH pathway inactivation promotes bladder cancer progression.The Journal of clinical investigation · 2015Trial
- Targeting mannosylation of nicastrin N-glycans attenuates γ-secretase activity and notch-dependent leukemia progression.The Journal of clinical investigation · 2026Article
- Ciclopirox reprograms effector responses and modulates Notch1 activation in activated human T cells.iScience · 2026Article
- Decoding NOTCH1: From T-Cell Development Guardian to Driver of Pediatric T-Cell Lymphoblastic Lymphoma.International journal of molecular sciences · 2026Review
- SMURF2 in Anticancer Therapy: Dual Role in Carcinogenesis and Theranostics.International journal of molecular sciences · 2026Review
- Nanomaterials for delivery of drugs and genes to disrupt notch signaling pathway in breast cancer.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- NOTCH1 combined with chemotherapy synergistically inhibits triple-negative breast cancer.World journal of clinical oncology · 2025Article
- The ESCRT protein CHMP5 promotes T cell leukemia by enabling BRD4-p300-dependent transcription.Nature communications · 2025Article
- Therapeutic targeting of the NOTCH1 and neddylation pathways in T cell acute lymphoblastic leukemia.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The Role of Notch Signaling and Gut Microbiota in Autoinflammatory Diseases: Mechanisms and Future Views.Biomedicines · 2025Review
- SIL-TAL1-Positive Adult T-ALL with t(11;14)(p15;q11.2): A Rare Case Report Highlighting Prognostic Challenges and Treatment Implications.Journal of inflammation research · 2025Article
- Loss of Notch dimerization perturbs intestinal homeostasis by a mechanism involving HDAC activity.PLoS genetics · 2024Article
- Notch Inhibitors and BH3 Mimetics in T-Cell Acute Lymphoblastic Leukemia.International journal of molecular sciences · 2024Review
- Unveiling promising targets in gastric cancer therapy: A comprehensive review.Molecular therapy. Oncology · 2024Review
- CD9 shapes glucocorticoid sensitivity in pediatric B-cell precursor acute lymphoblastic leukemia.Haematologica · 2024Article
- PIM1 is a potential therapeutic target for the leukemogenic effects mediated by JAK/STAT pathway mutations in T-ALL/LBL.NPJ precision oncology · 2024Article
- Developing Targeted Therapies for T Cell Acute Lymphoblastic Leukemia/Lymphoma.Current hematologic malignancy reports · 2023Review
- Inhibition of the NOTCH and mTOR pathways by nelfinavir as a novel treatment for T cell acute lymphoblastic leukemia.International journal of oncology · 2023Article
- Combination therapy of a PSEN1-selective γ-secretase inhibitor with dexamethasone and an XPO1 inhibitor to target T-cell acute lymphoblastic leukemia.Haematologica · 2023Article
- NOTCH signalling - a core regulator of bile duct disease?Disease models & mechanisms · 2023Review
188 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 8 institutions in 3 countries.
Funding
Abstract
Gamma-secretase inhibitors (GSIs) block the activation of the oncogenic protein Notch homolog-1 (NOTCH1) in T cell acute lymphoblastic leukemia (T-ALL). However, limited antileukemic cytotoxicity and severe gastrointestinal toxicity have restricted the clinical application of these targeted drugs. Here we show that combination therapy with GSIs plus glucocorticoids can improve the antileukemic effects of GSIs and reduce their gut toxicity in vivo. Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid receptor autoupregulation and induced apoptotic cell death through induction of the gene encoding BCL-2-like apoptosis initiator-11 (BCL2L11). GSI treatment resulted in cell cycle arrest and accumulation of goblet cells in the gut mediated by upregulation of the gene encoding the transcription factor Krüppel-like factor-4 (Klf4), a negative regulator of the cell cycle required for goblet cell differentiation. In contrast, glucocorticoid treatment induced transcriptional upregulation of cyclin D2 (Ccnd2) and protected mice from developing the intestinal goblet cell metaplasia typically induced by inhibition of NOTCH signaling with GSIs. These results support a role for glucocorticoids plus GSIs in the treatment of glucocorticoid-resistant T-ALL.
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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.