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

Annahita Sallmyr, Jinshui Fan, Kamal Datta, Kyu Tae Kim, Dan Grosu, Paul Shapiro, Donald Small, Feyruz Rassool

Research output: Contribution to journalArticle

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 doublestrand 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.

Original languageEnglish (US)
Pages (from-to)3173-3182
Number of pages10
JournalBlood
Volume111
Issue number6
DOIs
StatePublished - Mar 15 2008

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Acute Myeloid Leukemia
Protein-Tyrosine Kinases
DNA Damage
Reactive Oxygen Species
DNA
STAT5 Transcription Factor
Mutation
Genomic Instability
Repair
Cells
Cell Line
DNA Breaks
NADPH Oxidase
Receptor Protein-Tyrosine Kinases
Myeloid Cells
Guanosine Triphosphate
DNA Repair
Joining
Phosphotransferases
Chemical activation

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Internal tandem duplication of FLT3 (FLT3/ITD) induces increased ROS production, DNA damage, and misrepair : Implications for poor prognosis in AML. / Sallmyr, Annahita; Fan, Jinshui; Datta, Kamal; Kim, Kyu Tae; Grosu, Dan; Shapiro, Paul; Small, Donald; Rassool, Feyruz.

In: Blood, Vol. 111, No. 6, 15.03.2008, p. 3173-3182.

Research output: Contribution to journalArticle

Sallmyr, Annahita ; Fan, Jinshui ; Datta, Kamal ; Kim, Kyu Tae ; Grosu, Dan ; Shapiro, Paul ; Small, Donald ; Rassool, Feyruz. / Internal tandem duplication of FLT3 (FLT3/ITD) induces increased ROS production, DNA damage, and misrepair : Implications for poor prognosis in AML. In: Blood. 2008 ; Vol. 111, No. 6. pp. 3173-3182.
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