Cells expressing FLT3/ITD mutations exhibit elevated repair errors generated through alternative NHEJ pathways: implications for genomic instability and therapy
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- Jinshui Fan
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD; and
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- Li Li
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
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- Donald Small
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
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- Feyruz Rassool
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD; and
書誌事項
- 公開日
- 2010-12-09
- DOI
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- 10.1182/blood-2010-03-272591
- 公開者
- American Society of Hematology
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説明
<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>
収録刊行物
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- Blood
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Blood 116 (24), 5298-5305, 2010-12-09
American Society of Hematology
