Reactive oxygen species, DNA damage, and error-prone repair: A model for genomic instability with progression in myeloid leukemia?

F Rassool, T J Gaymes, N Omidvar, N Brady, S Beurlet, M Pla, M Reboul, N Lea, C Chomienne, N S B Thomas, G Mufti, R A Padua

    Research output: Contribution to journalArticlepeer-review

    135 Citations (Scopus)

    Abstract

    Myelodysplastic syndromes (MDS) comprise a heterogeneous group of disorders characterized by ineffective hematopoiesis, with an increased propensity to develop acute myelogenous leukemia (AML).Th e molecular basis for MDS progression is unknown, but a key element in MDS disease progression is loss of chromosomal material (genomic instability).U sing our twostep 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 errorprone repair of double-strand breaks (DSB) by nonhomologous end-joining.Ther e is a concomitant increase in reactive oxygen species (ROS) in these transgenic mice with disease progression. Importantly, RAC1, an essential component of the ROSproducing 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.Th ese data suggest treatment strategies that target RAS/RAC pathways and ROS production in human MDS/AML.
    Original languageEnglish
    Pages (from-to)8762 - 8771
    Number of pages10
    JournalCancer Research
    Volume67
    Issue number18
    DOIs
    Publication statusPublished - 15 Sept 2007

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