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

Rassool, Feyruz V., Gaymes, Terry J., Omidvar, Nader, Brady, Nichola, Beurlet, Stephanie, Pla, Marika, Reboul, Murielle, Lea, Nicholas, Chomienne, Christine, Thomas, Nicholas S. B., Mufti, Ghulam J. and Padua, Rose Anne 2007. Reactive Oxygen Species, DNA Damage, and Error-Prone Repair: A Model for Genomic Instability with Progression in Myeloid Leukemia? Cancer Research 67 (18) , pp. 8762-8771. 10.1158/0008-5472.CAN-06-4807

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Medicine
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords: Reactive oxygen species; DNA damage; DNA repair; error-prone non homologous end-joining; myeloid malignancies
Publisher: American Association for Cancer Research
ISSN: 0008-5472
Last Modified: 04 Jun 2017 02:09
URI: http://orca-mwe.cf.ac.uk/id/eprint/9878

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