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First published online 3 April 2007
doi: 10.1242/jcs.003152

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Inflammatory ROS promote and cooperate with the Fanconi anemia mutation for hematopoietic senescence

¹ Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
² Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA

^* Author for correspondence (e-mail: qishen.pang{at}cchmc.org)

Accepted 1 March 2007

The proinflammatory cytokine tumor necrosis factor (TNF) inhibits hematopoietic stem cell (HSC) expansion, interferes with HSC self-renewal and compromises the ability of HSC to reconstitute hematopoiesis. We have investigated mechanisms by which TNF suppresses hematopoiesis using the genomic instability syndrome Fanconi anemia mouse model deficient for the complementation-group-C gene (Fancc). Examination of senescence makers, such as senescence-associated -galactosidase, HP1-, p53 and p16^INK4A shows that TNF induces premature senescence in bone marrow HSCs and progenitor cells as well as other tissues of Fancc^–/– mice. TNF-induced senescence correlates with the accumulation of reactive oxygen species (ROS) and oxidative DNA damage. Neutralization of TNF or deletion of the TNF receptor in Fancc^–/– mice (Fancc^–/–;Tnfr1^–/–) prevents excessive ROS production and hematopoietic senescence. Pretreatment of TNF-injected Fancc^–/– mice with a ROS scavenger significantly reduces oxidative base damage, DNA strand breaks and senescence. Furthermore, HSCs and progenitor cells from TNF-treated Fancc^–/– mice show increased chromosomal aberrations and have an impaired oxidative DNA-damage repair. These results indicate an intimate link between inflammatory reactive oxygen species and DNA-damage-induced premature senescence in HSCs and progenitor cells, which may play an important role in aging and anemia.

Key words: DNA damage and repair, Fanconi anemia, Genomic instability, Hematopoietic stem cells, Inflammation, Reactive oxygen species

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