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 Blood, 15 March 2008, Vol. 111, No. 6, pp. 3173-3182.
Prepublished online as a Blood First Edition Paper on January 11, 2008; DOI 10.1182/blood-2007-05-092510.

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NEOPLASIA

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

Annahita Sallmyr1, Jinshui Fan1, Kamal Datta1, Kyu-Tae Kim2, Dan Grosu1, Paul Shapiro3, Donald Small2, and Feyruz Rassool1

1 Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore; 2 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD; and 3 School of Pharmacy, University of Maryland, Baltimore

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.


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