| http://purl.uniprot.org/citations/31790499 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/31790499 | http://www.w3.org/2000/01/rdf-schema#comment | "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."xsd:string |
| http://purl.uniprot.org/citations/31790499 | http://purl.org/dc/terms/identifier | "doi:10.1371/journal.pone.0225887"xsd:string |
| http://purl.uniprot.org/citations/31790499 | http://purl.uniprot.org/core/author | "Snyder D."xsd:string |
| http://purl.uniprot.org/citations/31790499 | http://purl.uniprot.org/core/author | "Shen K."xsd:string |
| http://purl.uniprot.org/citations/31790499 | http://purl.uniprot.org/core/author | "Smithgall T.E."xsd:string |
| http://purl.uniprot.org/citations/31790499 | http://purl.uniprot.org/core/author | "Cooper V.S."xsd:string |
| http://purl.uniprot.org/citations/31790499 | http://purl.uniprot.org/core/author | "Patel R.K."xsd:string |
| http://purl.uniprot.org/citations/31790499 | http://purl.uniprot.org/core/author | "Weir M.C."xsd:string |
| http://purl.uniprot.org/citations/31790499 | http://purl.uniprot.org/core/date | "2019"xsd:gYear |
| http://purl.uniprot.org/citations/31790499 | http://purl.uniprot.org/core/name | "PLoS One"xsd:string |
| http://purl.uniprot.org/citations/31790499 | http://purl.uniprot.org/core/pages | "e0225887"xsd:string |
| http://purl.uniprot.org/citations/31790499 | http://purl.uniprot.org/core/title | "Expression of myeloid Src-family kinases is associated with poor prognosis in AML and influences Flt3-ITD kinase inhibitor acquired resistance."xsd:string |
| http://purl.uniprot.org/citations/31790499 | http://purl.uniprot.org/core/volume | "14"xsd:string |
| http://purl.uniprot.org/citations/31790499 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/31790499 |
| http://purl.uniprot.org/citations/31790499 | http://xmlns.com/foaf/0.1/primaryTopicOf | https://pubmed.ncbi.nlm.nih.gov/31790499 |
| http://purl.uniprot.org/uniprot/#_A0A4P8K7E7-mappedCitation-31790499 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/31790499 |
| http://purl.uniprot.org/uniprot/#_A0A6G6D045-mappedCitation-31790499 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/31790499 |
| http://purl.uniprot.org/uniprot/#_A0A6G6D048-mappedCitation-31790499 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/31790499 |
| http://purl.uniprot.org/uniprot/#_A0A6G6D079-mappedCitation-31790499 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/31790499 |
| http://purl.uniprot.org/uniprot/#_A0A6G6D0I3-mappedCitation-31790499 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/31790499 |
| http://purl.uniprot.org/uniprot/#_A8K4G3-mappedCitation-31790499 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/31790499 |
| http://purl.uniprot.org/uniprot/#_B7Z6W7-mappedCitation-31790499 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/31790499 |
| http://purl.uniprot.org/uniprot/#_B7Z9D2-mappedCitation-31790499 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/31790499 |
| http://purl.uniprot.org/uniprot/#_P08631-mappedCitation-31790499 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/31790499 |