{"@context":{"@vocab":"https://cir.nii.ac.jp/schema/1.0/","rdfs":"http://www.w3.org/2000/01/rdf-schema#","dc":"http://purl.org/dc/elements/1.1/","dcterms":"http://purl.org/dc/terms/","foaf":"http://xmlns.com/foaf/0.1/","prism":"http://prismstandard.org/namespaces/basic/2.0/","cinii":"http://ci.nii.ac.jp/ns/1.0/","datacite":"https://schema.datacite.org/meta/kernel-4/","ndl":"http://ndl.go.jp/dcndl/terms/","jpcoar":"https://github.com/JPCOAR/schema/blob/master/2.0/"},"@id":"https://cir.nii.ac.jp/crid/1362544419922845184.json","@type":"Article","productIdentifier":[{"identifier":{"@type":"DOI","@value":"10.1182/blood-2010-03-272591"}},{"identifier":{"@type":"URI","@value":"http://ashpublications.org/blood/article-pdf/116/24/5298/1460982/zh805010005298.pdf"}}],"dc:title":[{"@value":"Cells expressing FLT3/ITD mutations exhibit elevated repair errors generated through alternative NHEJ pathways: implications for genomic instability and therapy"}],"description":[{"type":"abstract","notation":[{"@value":"<jats:title>Abstract</jats:title><jats:p>The internal tandem duplication (ITD) mutations of the FMS-like tyrosine kinase-3 (FLT3) receptor found in acute myeloid leukemia patients are associated with poor prognosis. Although DNA double-strand breaks (DSBs) are mainly repaired by the DNA-PK–dependent nonhomologous end-joining (NHEJ) pathway in normal mammalian cells, an alternative and less well-defined NHEJ pathway, characterized by microhomology at the repair junctions, play a role in the generation of deletions and translocations leading to cancer progression. Here we report that in FLT3/ITD-expressing cell lines and bone marrow mononuclear cells from FLT3/ITD knock-in mice, end-joining of DSBs occurs at microhomologous sequences resulting in a high frequency of DNA deletions. Strikingly, levels of Ku proteins, key components of the main NHEJ pathway, are decreased in FLT3/ITD+ cell lines and murine FLT3/ITD bone marrow mononuclear cells. Concomitantly, levels of DNA ligase IIIα, a component of ALT NHEJ, are increased in FLT3/ITD-expressing cells. Cells treated with a FLT3 inhibitor demonstrate decreased DNA ligase IIIα and a reduction in DNA deletions, suggesting that FLT3 signaling regulates the pathways by which DSBs are repaired. Thus, therapy to inhibit FLT3/ITD signaling and/or DNA ligase IIIα may lead to repair that reduces repair errors and genomic instability.</jats:p>"}]}],"creator":[{"@id":"https://cir.nii.ac.jp/crid/1382544419922845187","@type":"Researcher","foaf:name":[{"@value":"Jinshui Fan"}],"jpcoar:affiliationName":[{"@value":"Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD; and"}]},{"@id":"https://cir.nii.ac.jp/crid/1382544419922845185","@type":"Researcher","foaf:name":[{"@value":"Li Li"}],"jpcoar:affiliationName":[{"@value":"Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD"}]},{"@id":"https://cir.nii.ac.jp/crid/1382544419922845184","@type":"Researcher","foaf:name":[{"@value":"Donald Small"}],"jpcoar:affiliationName":[{"@value":"Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD"}]},{"@id":"https://cir.nii.ac.jp/crid/1382544419922845186","@type":"Researcher","foaf:name":[{"@value":"Feyruz Rassool"}],"jpcoar:affiliationName":[{"@value":"Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD; and"}]}],"publication":{"publicationIdentifier":[{"@type":"PISSN","@value":"00064971"},{"@type":"EISSN","@value":"15280020"}],"prism:publicationName":[{"@value":"Blood"}],"dc:publisher":[{"@value":"American Society of Hematology"}],"prism:publicationDate":"2010-12-09","prism:volume":"116","prism:number":"24","prism:startingPage":"5298","prism:endingPage":"5305"},"reviewed":"false","url":[{"@id":"http://ashpublications.org/blood/article-pdf/116/24/5298/1460982/zh805010005298.pdf"}],"createdAt":"2010-09-01","modifiedAt":"2021-11-07","relatedProduct":[{"@id":"https://cir.nii.ac.jp/crid/1360565168934576768","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Downstream molecular pathways of FLT3 in the pathogenesis of acute myeloid leukemia: biology and therapeutic implications"}]}],"dataSourceIdentifier":[{"@type":"CROSSREF","@value":"10.1182/blood-2010-03-272591"},{"@type":"CROSSREF","@value":"10.1186/1756-8722-4-13_references_DOI_QGExbpnXNtoPqEGcbtV5Vff5Y5A"}]}