Internal tandem duplication of FLT3 (FLT3/ITD) induces increased ROS production, DNA damage, and misrepair: implications for poor prognosis in AML

Blood. 2008 Mar 15;111(6):3173-82. doi: 10.1182/blood-2007-05-092510. Epub 2008 Jan 11.

Abstract

Activating mutations of the FMS-like tyrosine kinase-3 (FLT3) receptor occur in approximately 30% of acute myeloid leukemia (AML) patients and, at least for internal tandem duplication (ITD) mutations, are associated with poor prognosis. FLT3 mutations trigger downstream signaling pathways including RAS-MAP/AKT kinases and signal transducer and activator of transcription-5 (STAT5). We find that FLT3/ITD mutations start a cycle of genomic instability whereby increased reactive oxygen species (ROS) production leads to increased DNA double-strand breaks (DSBs) and repair errors that may explain aggressive AML in FLT3/ITD patients. Cell lines transfected with FLT3/ITD and FLT3/ITD-positive AML cell lines and primary cells demonstrate increased ROS. Increased ROS levels appear to be produced via STAT5 signaling and activation of RAC1, an essential component of ROS-producing NADPH oxidases. A direct association of RAC1-GTP binding to phosphorylated STAT5 (pSTAT5) provides a possible mechanism for ROS generation. A FLT3 inhibitor blocked increased ROS in FLT3/ITD cells resulting in decreased DSB and increased repair efficiency and fidelity. Our study suggests that the aggressiveness of the disease and poor prognosis of AML patients with FLT3/ITD mutations could be the result of increased genomic instability that is driven by higher endogenous ROS, increased DNA damage, and decreased end-joining fidelity.

Publication types

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

MeSH terms

  • Base Pair Mismatch / genetics*
  • Cell Line
  • DNA Damage / genetics*
  • Gene Duplication*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Leukemia, Erythroblastic, Acute / genetics
  • Leukemia, Erythroblastic, Acute / metabolism*
  • Leukemia, Erythroblastic, Acute / pathology
  • Prognosis
  • Reactive Oxygen Species / metabolism*
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction
  • fms-Like Tyrosine Kinase 3 / genetics
  • fms-Like Tyrosine Kinase 3 / metabolism*
  • rac1 GTP-Binding Protein / metabolism

Substances

  • Reactive Oxygen Species
  • STAT5 Transcription Factor
  • FLT3 protein, human
  • Flt3 protein, mouse
  • fms-Like Tyrosine Kinase 3
  • rac1 GTP-Binding Protein