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      FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress.

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          Abstract

          To understand the role of FoxO family members in hematopoiesis, we conditionally deleted FoxO1, FoxO3, and FoxO4 in the adult hematopoietic system. FoxO-deficient mice exhibited myeloid lineage expansion, lymphoid developmental abnormalities, and a marked decrease of the lineage-negative Sca-1+, c-Kit+ (LSK) compartment that contains the short- and long-term hematopoietic stem cell (HSC) populations. FoxO-deficient bone marrow had defective long-term repopulating activity that correlated with increased cell cycling and apoptosis of HSC. Notably, there was a marked context-dependent increase in reactive oxygen species (ROS) in FoxO-deficient HSC compared with wild-type HSC that correlated with changes in expression of genes that regulate ROS. Furthermore, in vivo treatment with the antioxidative agent N-acetyl-L-cysteine resulted in reversion of the FoxO-deficient HSC phenotype. Thus, FoxO proteins play essential roles in the response to physiologic oxidative stress and thereby mediate quiescence and enhanced survival in the HSC compartment, a function that is required for its long-term regenerative potential.

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          Author and article information

          Journal
          Cell
          Cell
          Elsevier BV
          0092-8674
          0092-8674
          Jan 26 2007
          : 128
          : 2
          Affiliations
          [1 ] Division of Hematology, Department of Medicine, Brigham and Women's Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
          Article
          S0092-8674(07)00050-5
          10.1016/j.cell.2007.01.003
          17254970
          567e3740-9fca-4667-bb0d-fcd7681783d7
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