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Reactive Oxygen Species, DNA Damage, and Error-Prone Repair: A Model for Genomic Instability with Progression in Myeloid Leukemia?

¹ Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland; ² King's College London, Department of Haematological Medicine, Leukemia Sciences Laboratories, The Rayne Institute, GKT School of Medicine, Denmark Hill Campus, London, United Kingdom; ³ School of Biosciences, Cardiff University, Cardiff, United Kingdom; and ⁴ INSERM U718, Institût Universitaire d'Hématologie, IFR 105, Hôpital Saint-Louis, Paris, France

Requests for reprints: Feyruz Rassool, University of Maryland School of Medicine, Department of Radiation Oncology, 655 West Baltimore Street, BRB 7-009, Baltimore, MD 21201-1509. Phone: 410-706-5337; Fax: 410-706-3000; E-mail: frassool{at}som.umaryland.edu or Rose Ann Padua, Institut National de la Sante et de la Recherche Medicale (INSERM) U718, Institût Universitaire d'Hématologie, Hôpital Saint Louis, 75010 Paris, France. Phone: 33-1-53-72-40-18; Fax: 33-1-53-72-40-16.

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of disorders characterized by ineffective hematopoiesis, with an increased propensity to develop acute myelogenous leukemia (AML). The molecular basis for MDS progression is unknown, but a key element in MDS disease progression is loss of chromosomal material (genomic instability). Using our two-step mouse model for myeloid leukemic disease progression involving overexpression of human mutant NRAS and BCL2 genes, we show that there is a stepwise increase in the frequency of DNA damage leading to an increased frequency of error-prone repair of double-strand breaks (DSB) by nonhomologous end-joining. There is a concomitant increase in reactive oxygen species (ROS) in these transgenic mice with disease progression. Importantly, RAC1, an essential component of the ROS-producing NADPH oxidase, is downstream of RAS, and we show that ROS production in NRAS/BCL2 mice is in part dependent on RAC1 activity. DNA damage and error-prone repair can be decreased or reversed in vivo by N-acetyl cysteine antioxidant treatment. Our data link gene abnormalities to constitutive DNA damage and increased DSB repair errors in vivo and provide a mechanism for an increase in the error rate of DNA repair with MDS disease progression. These data suggest treatment strategies that target RAS/RAC pathways and ROS production in human MDS/AML. [Cancer Res 2007;67(18):8762–71]

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