Cells expressing FLT3/ITD mutations exhibit elevated repair errors generated through alternative NHEJ pathways: implications for genomic instability and therapy

Blood. 2010 Dec 9;116(24):5298-305. doi: 10.1182/blood-2010-03-272591. Epub 2010 Aug 31.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells
  • DNA Breaks, Double-Stranded
  • DNA Ligase ATP
  • DNA Ligases / analysis
  • DNA Repair*
  • Disease Progression
  • Genomic Instability*
  • Humans
  • Inverted Repeat Sequences*
  • Leukemia, Myeloid, Acute / genetics*
  • Mice
  • Poly-ADP-Ribose Binding Proteins
  • Xenopus Proteins
  • fms-Like Tyrosine Kinase 3 / genetics*


  • Poly-ADP-Ribose Binding Proteins
  • Xenopus Proteins
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • DNA Ligases
  • DNA Ligase ATP
  • DNA ligase III alpha protein, Xenopus