Reactive oxygen species, DNA damage, and error-prone repair: a model for genomic instability with progression in myeloid leukemia?
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.
Rassool
Feyruz V
FV
Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland 21201-1509, USA. frassool@som.umaryland.edu
Gaymes
Terry J
TJ
Omidvar
Nader
N
Brady
Nicola
N
Beurlet
Stephanie
S
Pla
Marika
M
Reboul
Murielle
M
Lea
Nicholas
N
Chomienne
Christine
C
Thomas
Nicholas S B
NS
Mufti
Ghulam J
GJ
Padua
Rose Ann
RA
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*
D017382:Reactive Oxygen Species