ArticlePloS one2014
Activating FLT3 mutants show distinct gain-of-function phenotypes in vitro and a characteristic signaling pathway profile associated with prognosis in acute myeloid leukemia.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 69 citations in OpenAlex.
- Constraining regulatory domain dynamics of the Src kinase Fgr increases ATP-site inhibitor sensitivity and impairs bone marrow engraftment.Cell reports · 2026Article
- Targeted Therapy in Acute Myeloid Leukemia: Current Approaches and Novel Directions.Journal of personalized medicine · 2026Review
- Constitutive activation of the Src-family kinases Fgr and Hck enhances the tumor burden of acute myeloid leukemia cells in immunocompromised mice.Scientific reports · 2025Article
- Precision medicine in AML: overcoming resistance.International journal of hematology · 2024Review
- Synergistic effect of FMS-like tyrosine kinase-3 (FLT3) inhibitors combined with a CDK7 inhibitor in FLT3-ITD-mutated acute myeloid leukemia.Blood cancer journal · 2024Article
- Common Driver Mutations in AML: Biological Impact, Clinical Considerations, and Treatment Strategies.Cells · 2024Review
- Non-canonical FLT3 alterations reveal novel germline FLT3 variants leading to somatic gene rescue mutations.Blood cancer journal · 2024Article
- BRCC36 associates with FLT3-ITD to regulate its protein stability and intracellular signaling in acute myeloid leukemia.Cancer science · 2024Article
- Comprehensive Molecular Profiling of NPM1-Mutated Acute Myeloid Leukemia Using RNAseq Approach.International journal of molecular sciences · 2024Article
- RUNX1 loss renders hematopoietic and leukemic cells dependent on IL-3 and sensitive to JAK inhibition.The Journal of clinical investigation · 2023Article
- DNA damage accumulation and repair defects in FLT3-ITD acute myeloid leukemia: Implications for clonal evolution and disease progression.Hematological oncology · 2023Review
- Sitravatinib as a potent FLT3 inhibitor can overcome gilteritinib resistance in acute myeloid leukemia.Biomarker research · 2023Article
- Outcomes of Patients with FLT3 Positive Acute Myeloid Leukaemia; an Experience from a Tertiary Care Hospital in Karachi, Pakistan.Journal of cancer & allied specialties · 2023Article
- Clinical and molecular features of FLT3 juxtamembrane domain missense mutations in acute myeloid leukaemia.Journal of cellular and molecular medicine · 2022Article
- Epigenetic downregulation of Socs2 contributes to mutant N-Ras-mediated hematopoietic dysregulation.Disease models & mechanisms · 2022Article
- Review
- A review of FLT3 inhibitors in acute myeloid leukemia.Blood reviews · 2022Review
- Straight to the Point-The Novel Strategies to Cure Pediatric AML.International journal of molecular sciences · 2022Review
- Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches.OncoTargets and therapy · 2022Review
- Murine Models of Acute Myeloid Leukemia.Frontiers in oncology · 2022Review
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Authors and funding
14 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
About 30% of patients with acute myeloid leukemia (AML) harbour mutations of the receptor tyrosine kinase FLT3, mostly internal tandem duplications (ITD) and point mutations of the second tyrosine kinase domain (TKD). It was the aim of this study to comprehensively analyze clinical and functional properties of various FLT3 mutants. In 672 normal karyotype AML patients FLT3-ITD, but not FLT3-TKD mutations were associated with a worse relapse free and overall survival in multivariate analysis. In paired diagnosis-relapse samples FLT3-ITD showed higher stability (70%) compared to FLT3-TKD (30%). In vitro, FLT3-ITD induced a strong activating phenotype in Ba/F3 cells. In contrast, FLT3-TKD mutations and other point mutations--including two novel mutations--showed a weaker but clear gain-of-function phenotype with gradual increase in proliferation and protection from apoptosis. The pro-proliferative capacity of the investigated FLT3 mutants was associated with cell surface expression and tyrosine 591 phosphorylation of the FLT3 receptor. Western blot experiments revealed STAT5 activation only in FLT3-ITD positive cell lines, in contrast to FLT3-non-ITD mutants, which displayed an enhanced signal of AKT and MAPK activation. Gene expression analysis revealed distinct difference between FLT3-ITD and FLT3-TKD for STAT5 target gene expression as well as deregulation of SOCS2, ENPP2, PRUNE2 and ART3. FLT3-ITD and FLT3 point mutations show a gain-of-function phenotype with distinct signalling properties in vitro. Although poor prognosis in AML is only associated with FLT3-ITD, all activating FLT3 mutations can contribute to leukemogenesis and are thus potential targets for therapeutic interventions.
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