ArticleBlood2006
Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD.
Article in Blood, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 133 citations in OpenAlex.
- Counter-Therapeutic Strategies for Resistance of FLT3 Inhibitors in Acute Myeloid Leukemia.Cells · 2025Review
- DistinctInternational journal of molecular sciences · 2024Article
- Paclitaxel mediates the PI3K/AKT/mTOR pathway to reduce proliferation of FLT3‑ITDExperimental and therapeutic medicine · 2024Article
- Foretinib Is Effective in Acute Myeloid Leukemia by Inhibiting FLT3 and Overcoming Secondary Mutations That Drive Resistance to Quizartinib and Gilteritinib.Cancer research · 2024Article
- Distinct roles of hematopoietic cytokines in the regulation of leukemia stem cells in murine MLL-AF9 leukemia.Stem cell reports · 2024Article
- Whole exome sequencing of pediatric leukemia reveals a novel InDel within FLT-3 gene in AML patient from Mizo tribal population, Northeast India.BMC genomic data · 2022Article
- The IL-3, IL-5, and GM-CSF common receptor beta chain mediates oncogenic activity of FLT3-ITD-positive AML.Leukemia · 2022Article
- Disrupting PTPRJ transmembrane-mediated oligomerization counteracts oncogenic receptor tyrosine kinase FLT3 ITD.Frontiers in oncology · 2022Article
- Point Mutations in theFrontiers in oncology · 2022Article
- Molecular Targeted Therapy and Immunotherapy for Myelodysplastic Syndrome.International journal of molecular sciences · 2021Review
- Therapeutic targeting of FLT3 and associated drug resistance in acute myeloid leukemia.Journal of hematology & oncology · 2020Review
- Pharmacological Inhibition of Oncogenic STAT3 and STAT5 Signaling in Hematopoietic Cancers.Cancers · 2020Review
- Melatonin enhances sorafenib-induced cytotoxicity in FLT3-ITD acute myeloid leukemia cells by redox modification.Theranostics · 2019Article
- The Cooperative Relationship between STAT5 and Reactive Oxygen Species in Leukemia: Mechanism and Therapeutic Potential.Cancers · 2018Review
- Internal tandem duplication mutations in the tyrosine kinase domain of FLT3 display a higher oncogenic potential than the activation loop D835Y mutation.Annals of hematology · 2018Article
- ITD mutation in FLT3 tyrosine kinase promotes Warburg effect and renders therapeutic sensitivity to glycolytic inhibition.Leukemia · 2017Article
- FLT3-ITD and its current role in acute myeloid leukaemia.Medical oncology (Northwood, London, England) · 2017Review
- The Future of Targeting FLT3 Activation in AML.Current hematologic malignancy reports · 2017Review
- Prolonged cellular midostaurin retention suggests potential alternative dosing strategies for FLT3-ITD-positive leukemias.Leukemia · 2016Article
- Lineage-specific STAT5 target gene activation in hematopoietic progenitor cells predicts the FLT3(+)-mediated leukemic phenotype.Leukemia · 2016Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Acquired mutations in the FLT3 receptor tyrosine kinase are common in acute myeloid leukemia and result in constitutive activation. The most frequent mechanism of activation is disruption of the juxtamembrane autoregulatory domain by internal tandem duplications (ITDs). FLT3-ITDs confer factor-independent growth to hematopoietic cells and induce a myeloproliferative syndrome in murine bone marrow transplant models. We and others have observed that FLT3-ITD activates STAT5 and its downstream effectors, whereas ligand-stimulated wild-type FLT3 (FLT3WT) does not. In vitro mapping of tyrosine phosphorylation sites in FLT3-ITD identified 2 candidate STAT5 docking sites within the juxtamembrane domain that are disrupted by the ITD. Tyrosine to phenylalanine substitution of residues 589 and 591 in the context of the FLT3-ITD did not affect tyrosine kinase activity, but abrogated STAT5 activation. Furthermore, FLT3-ITD-Y589/591F was incapable of inducing a myeloproliferative phenotype when transduced into primary murine bone marrow cells, whereas FLT3-ITD induced myeloproliferative disease with a median latency of 50 days. Thus, the conformational change in the FLT3 juxtamembrane domain induced by the ITD activates the kinase through dysregulation of autoinhibition and results in qualitative differences in signal transduction through STAT5 that are essential for the transforming potential of FLT3-ITD in vivo.
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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 Socratic graph.