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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. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-05-092510v1 111/6/3173    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sallmyr, A. Articles by Rassool, F. Search for Related Content PubMed PubMed Citation Articles by Sallmyr, A. Articles by Rassool, F. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 29, 2007 Accepted December 30, 2007 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, and Feyruz Rassool* Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, United States Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States School of Pharmacy, University of Maryland, Baltimore, MD, United States * Corresponding author; email: frassool{at}som.umaryland.edu. 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 increase DNA double strand breaks (DSB) 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 oxidase. 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. Schmidt-Arras, S.-A. Bohmer, S. Koch, J. P. Muller, L. Blei, H. Cornils, R. Bauer, S. Korasikha, C. Thiede, and F.-D. Bohmer Anchoring of FLT3 in the endoplasmic reticulum alters signaling quality Blood, April 9, 2009; 113(15): 3568 - 3576. [Abstract] [Full Text] [PDF] Y. Gao, A. Howard, K. Ban, and J. Chandra Oxidative Stress Promotes Transcriptional Up-regulation of Fyn in BCR-ABL1-expressing Cells J. Biol. Chem., March 13, 2009; 284(11): 7114 - 7125. [Abstract] [Full Text] [PDF] A. T. J. Wierenga, E. Vellenga, and J. J. Schuringa Maximal STAT5-Induced Proliferation and Self-Renewal at Intermediate STAT5 Activity Levels Mol. Cell. Biol., November 1, 2008; 28(21): 6668 - 6680. [Abstract] [Full Text] [PDF]

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