期刊
BLOOD
卷 116, 期 24, 页码 5298-5305出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-03-272591
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- University of Maryland Cancer Center
- National Institutes of Health [CA90668, CA70970]
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 III alpha, a component of ALT NHEJ, are increased in FLT3/ITD-expressing cells. Cells treated with a FLT3 inhibitor demonstrate decreased DNA ligase III alpha 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 III alpha may lead to repair that reduces repair errors and genomic instability. (Blood. 2010;116(24):5298-5305)
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