Author/Authors :
Zuzana Tothova، نويسنده , , Ramya Kollipara، نويسنده , , Brian J. Huntly، نويسنده , , Benjamin H. Lee، نويسنده , , Diego H. Castrillon، نويسنده , , Dana E. Cullen، نويسنده , , Elizabeth P. McDowell، نويسنده , , Suzan Lazo-Kallanian، نويسنده , , Ifor R. Williams، نويسنده , , Christopher Sears، نويسنده , , Scott A. Armstrong، نويسنده , , Emmanuelle Passegué، نويسنده , , Ronald A. DePinho، نويسنده , , D. Gary Gilliland، نويسنده ,
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.
