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JCS ePress online publication date 3 Apr 2007
doi: 10.1242/jcs.003152

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Research Article

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


Xiaoling Zhang, Daniel P. Sejas, Yuhui Qiu, David A. Williams, and Qishen Pang*
* Author for correspondence (e-mail: qishen.pang{at}cchmc.org)

The proinflammatory cytokine tumor necrosis factor {alpha} (TNF{alpha}) 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{alpha} 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 {beta}-galactosidase, HP1-{gamma}, p53 and p16INK4A shows that TNF{alpha} induces premature senescence in bone marrow HSCs and progenitor cells as well as other tissues of Fancc-/- mice. TNF{alpha}-induced senescence correlates with the accumulation of reactive oxygen species (ROS) and oxidative DNA damage. Neutralization of TNF{alpha} or deletion of the TNF receptor in Fancc-/- mice (Fancc-/-;Tnfr1-/-) prevents excessive ROS production and hematopoietic senescence. Pretreatment of TNF{alpha}-injected Fancc-/- mice with a ROS scavenger significantly reduces oxidative base damage, DNA strand breaks and senescence. Furthermore, HSCs and progenitor cells from TNF{alpha}-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.


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© The Company of Biologists Ltd 2007