ArticleOncotarget2017
Combined inhibition of GLI and FLT3 signaling leads to effective anti-leukemic effects in human acute myeloid leukemia.
Article in Oncotarget, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 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
19 citing papers in PubMed, 33 citations in OpenAlex.
- Review
- Selective EV Protein Sorting and Pathway Perturbation in AML Upon Synergistic FLT3 and Hedgehog Pathway Inhibition.Journal of extracellular vesicles · 2025Article
- Review
- Acute myeloid leukemia: from NGS, through scRNA-seq, to CAR-T. dissect cancer heterogeneity and tailor the treatment.Journal of experimental & clinical cancer research : CR · 2023Review
- High GLI-1 Expression is a Reliable Indicator of Bad Prognosis in Newly Diagnosed Acute Leukemia Patients.Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion · 2023Article
- The hedgehog pathway in hematopoiesis and hematological malignancy.Frontiers in oncology · 2022Review
- Hedgehog/GLI signaling in hematopoietic development and acute myeloid leukemia-From bench to bedside.Frontiers in cell and developmental biology · 2022Review
- The BET bromodomain inhibitor ZEN-3365 targets the Hedgehog signaling pathway in acute myeloid leukemia.Annals of hematology · 2021Article
- Mebendazole Mediates Proteasomal Degradation of GLI Transcription Factors in Acute Myeloid Leukemia.International journal of molecular sciences · 2021Article
- Hedgehog Signaling in Myeloid Malignancies.Cancers · 2021Review
- Understanding the Hedgehog Signaling Pathway in Acute Myeloid Leukemia Stem Cells: A Necessary Step toward a Cure.Biology · 2021Review
- Article
- Downregulation of GLI3 Expression Mediates Chemotherapy Resistance in Acute Myeloid Leukemia.International journal of molecular sciences · 2020Article
- Review
- Review
- Role of GLI Transcription Factors in Pathogenesis and Their Potential as New Therapeutic Targets.International journal of molecular sciences · 2018Review
- Targeting Transcription Factors for Cancer Treatment.Molecules (Basel, Switzerland) · 2018Review
- Targeting GLI Transcription Factors in Cancer.Molecules (Basel, Switzerland) · 2018Review
- Analysis of hedgehog signaling in periocular sebaceous carcinoma.Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie · 2018Observational
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Activation of the Hedgehog pathway has been implicated in the pathogenesis of several tumor types including myeloid leukemia. Previously we demonstrated that overexpression of Hedgehog downstream mediators GLI1/2 confers an adverse prognosis to patients with acute myeloid leukemia (AML) and is correlated with a FLT3 mutated status. To analyze a possible non-canonical activation of the Hedgehog pathway via FLT3 and PI3K, we performed blocking experiments utilizing inhibitors for FLT3 (sunitinib), PI3K (PF-04691502) and GLI1/2 (GANT61) in FLT3-mutated and FLT3 wildtype AML cell lines and primary blasts. Combination of all three compounds had stronger anti-leukemic effects in FLT3-mutated compared to FLT3 wildtype AML cells in vitro. Interestingly, the colony growth of normal CD34+ cells from healthy donors was not impeded by the triple inhibitor combination possibly opening a therapeutic window for the clinical use of inhibitor combinations. Besides, combined treatment with sunitinib, PF-04691502 and GANT61 significantly prolonged the survival of mice transplanted with FLT3-mutated MV4-11 cells compared to the single agent treatments. Furthermore, the inhibition of FLT3 and PI3K resulted in reduced GLI protein expression and promotor activity in FLT3-mutated but not in FLT3 wildtype AML cell lines in western blotting and GLI1/2 promoter assays supporting our hypothesis of non-canonical GLI activation via FLT3.In summary, FLT3-mutated in contrast to FLT3 wildtype cells or normal human hematopoietic progenitor cells are exquisitely sensitive to combined inhibition by FLT3, PI3K and GLI1/2 overcoming some of the limitations of current FLT3 directed therapy in AML. The development of GLI1/2 inhibitors is highly desirable.
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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.