ArticleBlood2016
Targeting FLT3-ITD signaling mediates ceramide-dependent mitophagy and attenuates drug resistance in AML.
Article in Blood, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 125 papers, 3 of them syntheses that pooled it.
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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.
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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
125 citing papers in PubMed, 3 syntheses or guidelines pooled it, 192 citations in OpenAlex.
- The molecular mechanisms of mitochondrial dynamics and mitophagy and their complex association with cancer drug resistance.Journal of translational medicine · 2025Pooled it
- A global bibliometric and visualized analysis of the links between the autophagy and acute myeloid leukemia.Frontiers in pharmacology · 2023Pooled it
- Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)Autophagy · 2021Guideline
- Targeting mitochondrial quality control in diabetic kidney disease: emerging therapeutic opportunities.Renal failure · 2026Review
- Drugging small-molecule compounds in autophagy-dependent cell death to overcome cancer therapy resistance.Apoptosis : an international journal on programmed cell death · 2026Review
- Article
- Mechanism of Silybin in Alleviating Liver Damage Induced by Heat Stress of Peking Ducks.Animals : an open access journal from MDPI · 2026Article
- Sphingolipid Metabolism in Obesity: Bidirectional Regulation and Comparative Perspectives on Plant Sphingolipids.Nutrients · 2026Review
- Mechanisms and Therapeutic Potential of Targeting Mitophagy in Neurodegenerative Diseases.Molecular neurobiology · 2026Review
- Realgar Transforming Solution as a Novel Arsenic Agent Triggers PINK1/Parkin-Dependent Mitophagy and Apoptosis in the Molm-13 Acute Myeloid Leukemia Cell Line.Biological trace element research · 2026Article
- Sphingosine-1-phosphate receptor modulators resensitize FLT3-ITD acute myeloid leukemia cells with NRAS mutations to FLT3 inhibitors.Leukemia · 2026Article
- Comprehensive bioinformatics analysis targeting sphingosine-related genes in head and neck cancer.Discover oncology · 2026Article
- Acid ceramidase inhibition enhances BCL-2 targeting in venetoclax-resistant acute myeloid leukemia.Blood neoplasia · 2026Article
- Mitochondrial dynamics and cancer: mechanisms and targeted therapy.Cell biology and toxicology · 2026Review
- Metabolites beyond metabolism: Exploring their atypical roles in protein modification and signaling transduction.Chinese medical journal · 2026Review
- The small GTPase ARF6 regulates sphingolipid homeostasis and supports proliferation in acute myeloid leukemia.Haematologica · 2026Article
- Mitochondria in focus: From structure and function to their role in human diseases. A review.Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia · 2025Review
- Mitophagy-mediated S1P facilitates muscle adaptive responses to endurance exercise through SPHK1-S1PR1/S1PR2 in slow-twitch myofibers.Autophagy · 2025Article
- Metabolic Signature ofJournal of personalized medicine · 2025Review
- Mitochondrial Quality Control in Neurodegeneration and Cancer: A Common Denominator, Distinct Therapeutic Challenges.International journal of molecular sciences · 2025Review
65 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
Signaling pathways regulated by mutant Fms-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD), which mediate resistance to acute myeloid leukemia (AML) cell death, are poorly understood. Here, we reveal that pro-cell death lipid ceramide generation is suppressed by FLT3-ITD signaling. Molecular or pharmacologic inhibition of FLT3-ITD reactivated ceramide synthesis, selectively inducing mitophagy and AML cell death. Mechanistically, FLT3-ITD targeting induced ceramide accumulation on the outer mitochondrial membrane, which then directly bound autophagy-inducing light chain 3 (LC3), involving its I35 and F52 residues, to recruit autophagosomes for execution of lethal mitophagy. Short hairpin RNA (shRNA)-mediated knockdown of LC3 prevented AML cell death in response to FLT3-ITD inhibition by crenolanib, which was restored by wild-type (WT)-LC3, but not mutants of LC3 with altered ceramide binding (I35A-LC3 or F52A-LC3). Mitochondrial ceramide accumulation and lethal mitophagy induction in response to FLT3-ITD targeting was mediated by dynamin-related protein 1 (Drp1) activation via inhibition of protein kinase A-regulated S637 phosphorylation, resulting in mitochondrial fission. Inhibition of Drp1 prevented ceramide-dependent lethal mitophagy, and reconstitution of WT-Drp1 or phospho-null S637A-Drp1 but not its inactive phospho-mimic mutant (S637D-Drp1), restored mitochondrial fission and mitophagy in response to crenolanib in FLT3-ITD
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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.