ArticlePloS one2019
Expression of myeloid Src-family kinases is associated with poor prognosis in AML and influences Flt3-ITD kinase inhibitor acquired resistance.
Article in PloS one, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 32 citations in OpenAlex.
- Experimental evaluation of Nilotinib and Paclitaxel co-delivered via albumin nanoparticles as a therapeutic strategy for lung squamous cell carcinoma.Clinical and experimental medicine · 2026Article
- Constraining regulatory domain dynamics of the Src kinase Fgr increases ATP-site inhibitor sensitivity and impairs bone marrow engraftment.Cell reports · 2026Article
- Lactate metabolism and epigenetic reprogramming drive c-KIT hyperactivation to mediate Gilteritinib resistance: Rationale for c-KIT degraders over kinase inhibitors.Acta pharmaceutica Sinica. B · 2026Article
- Src inhibition potentiates MCL-1 antagonist activity in acute myeloid leukemia.Signal transduction and targeted therapy · 2025Article
- 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
- An SH3-binding allosteric modulator stabilizes the global conformation of the AML-associated Src-family kinase, Hck.The Journal of biological chemistry · 2025Article
- Bioinformatics-guided construction of a tumor microenvironment-derived prognostic model in acute myeloid leukemia.PloS one · 2025Article
- Network-based analysis and experimental validation of identified natural compounds from Yinchen Wuling San for acute myeloid leukemia.Frontiers in pharmacology · 2025Article
- Cocrystallization of the Src-Family Kinase Hck with the ATP-Site Inhibitor A-419259 Stabilizes an Extended Activation Loop Conformation.Biochemistry · 2024Article
- CD3ζ-Mediated Signaling Protects Retinal Ganglion Cells in Glutamate Excitotoxicity of the Retina.Cells · 2024Article
- Osimertinib Covalently Binds to CD34 and Eliminates Myeloid Leukemia Stem/Progenitor Cells.Cancer research · 2024Article
- AML under the Scope: Current Strategies and Treatment Involving FLT3 Inhibitors and Venetoclax-Based Regimens.International journal of molecular sciences · 2023Review
- Review
- RUNX1 colludes with NOTCH1 to reprogram chromatin in T cell acute lymphoblastic leukemia.iScience · 2023Article
- Article
- ATP-site inhibitors induce unique conformations of the acute myeloid leukemia-associated Src-family kinase, Fgr.Structure (London, England : 1993) · 2022Article
- Inflammatory response mediates cross-talk with immune function and reveals clinical features in acute myeloid leukemia.Bioscience reports · 2022Article
- Molecular determinants of etoposide resistance in HL60 cells.Bioinformation · 2022Article
- Whole genome, exon mutation and transcriptomic profiling of acute myeloid leukemia: A case report.Oncology letters · 2021Article
- New Structural Perspectives in G Protein-Coupled Receptor-Mediated Src Family Kinase Activation.International journal of molecular sciences · 2021Review
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Unregulated protein-tyrosine kinase signaling is a common feature of AML, often involving mutations in Flt3 and overexpression of myeloid Src-family kinases (Hck, Fgr, Lyn). Here we show that high-level expression of these Src kinases predicts poor survival in a large cohort of AML patients. To test the therapeutic benefit of Flt3 and Src-family kinase inhibition, we used the pyrrolopyrimidine kinase inhibitor A-419259. This compound potently inhibits Hck, Fgr, and Lyn as well as Flt3 bearing an activating internal tandem duplication (ITD). Flt3-ITD expression sensitized human TF-1 myeloid cells to growth arrest by A-419259, supporting direct action on the Flt3-ITD kinase domain. Cells transformed with the Flt3-ITD mutants D835Y and F691L were resistant to A-419259, while co-expression of Hck or Fgr restored inhibitor sensitivity to Flt3-ITD D835Y. Conversely, Hck and Fgr mutants with engineered A-419259 resistance mutations decreased sensitivity of TF-1/Flt3-ITD cells. To investigate de novo resistance mechanisms, A-419259-resistant Flt3-ITD+ AML cell populations were derived via long-term dose escalation. Whole exome sequencing identified a distinct Flt3-ITD kinase domain mutation (N676S/T) among all A-419259 target kinases in each of six independent resistant cell populations. These studies show that Hck and Fgr expression influences inhibitor sensitivity and the pathway to acquired resistance in Flt3-ITD+ AML.
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