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The role of reactive oxygen and nitrogen species in the development of Fanconi Anemia, an inherited bone marrow failure disorder Hadjur, Suzana

Abstract

The objective of this thesis was to investigate the role of endogenous reactive oxygen and nitrogen species in the pathogenesis of Fanconi's Anemia (FA) using Fanconi Anemia Complementation Group C (Fancc) - deficient mice. This objective was examined in two distinct ways. First, through the generation and characterization of a novel mouse model for FA with intrinsic oxidant stress and secondly, through the observation that nitric oxide (NO) may have a role in cytokine - mediated inhibition of hematopoiesis in FA. FA is an autosomal recessive disorder, which primarily affects children and young adults, resulting in morbidity and mortality due to B M failure or acute myelogenous leukemia (AML). Currently, eight complementation groups have been identified and six FA genes have been cloned. Although knockout mice have been generated for each of the genes cloned, they do not exhibit the primary hematopoietic defect of FA. Thus, no spontaneously occurring mouse model for FA exists with which to better define the pathogenesis of this disease. Several lines of evidence have pointed to abnormal regulation of intracellular reactive oxygen species (ROS) in individuals with FA. To investigate the possible role of the Fancc protein in the regulation of an in vivo redox state, mice were generated having combined deficiencies in the genes encoding the cytoplasmic antioxidant, Cu/Zn superoxide dismutase (Sod1) and Fancc. Fancc⁻[sup /]⁻Sod1⁻[sup /]⁻ mice developed hepatic lipid accumulation, peripheral blood bicytopenia, marrow hypocellularity, little to no growth of committed progenitor cells in vitro, and decreased frequencies of long-term progenitors. This novel murine model of FA partially replicates the hematopoietic defect of this disease and may be useful in defining novel therapies. The second theme of this thesis involved the observation that NO may have a role in FA BM failure. Cytokine inhibition of hematopoietic progenitor colony growth from Fancc⁻[sup /]⁻ mice was completely rescued in the presence of an iNOS inhibitor, L-NMMA. Fancc⁻[sup /]⁻ progenitor cells were hypersensitive to NO generating drugs in vitro while primary macrophages had elevated expression of iNOS and NO production in response to IFNγ and IFNγ/LPS. To date, no information exists regarding FA and NO and these studies have opened a new avenue of investigation in FA research.

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