title: Reactive oxygen species, DNA damage, and error-prone repair: a model for genomic instability with progression in myeloid leukemia?
abstract: 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.
authors: Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland 21201-1509, USA. frassool@som.umaryland.edu
authors: Feyruz V
authors: FV
authors: Rassool
authors: Terry J
authors: TJ
authors: Gaymes
authors: Nader
authors: N
authors: Omidvar
authors: Nicola
authors: N
authors: Brady
authors: Stephanie
authors: S
authors: Beurlet
authors: Marika
authors: M
authors: Pla
authors: Murielle
authors: M
authors: Reboul
authors: Nicholas
authors: N
authors: Lea
authors: Christine
authors: C
authors: Chomienne
authors: Nicholas S B
authors: NS
authors: Thomas
authors: Ghulam J
authors: GJ
authors: Mufti
authors: Rose Ann
authors: RA
authors: Padua
mesh_terms: D000818:Animals; D004249:DNA Damage; D004260:DNA Repair; D004195:Disease Models, Animal; D018450:Disease Progression; D019254:Genes, bcl-2; D011905:Genes, ras; D042822:Genomic Instability; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species