FoxOs Are Critical Mediators of Hematopoietic Stem Cell Resistance to Physiologic Oxidative Stress

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.

Expression pattern and transcriptional regulatory mechanism of noxa gene in grass carp (Ctenopharyngodon idella)

“…FOXO1 protein is implicated in diverse cellular activities including DNA repair, oxidative stress resistance, and apoptosis [31,32]. Moreover, enhanced FOXO1 transcription activity is required to promote apoptosis and cell cycle [33].…”

The FoxO transcription factors and metabolic regulation

“…These extensive studies suggest that tumor formation needs inactivation of all three FoxOs due to extensive functional redundancy and that FoxO1 is the most physiologically important regulator of endothelial stability, which is consistent with FoxO1À/À mice. Furthermore, the findings that Mx-Cre + ; FoxO1/3/4 L/L showed abnormalities of the hematopoietic system, which were not observed in single or double knockout mutants of FoxOs, suggest the functional redundancy in hematopoietic system and a critical role for FoxOs in this system [64].…”

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

“…Foxo regulates quiescence and survival in response to oxidative stress. 189,190 Another important gene involved in HSC and leukemia CICs is promyelocytic leukemia (PML). The PML gene is involved in the t(15:17) chromosomal translocation found in acute promyelocytic leukemia.…”