TY - JOUR
T1 - FoxOs Are Critical Mediators of Hematopoietic Stem Cell Resistance to Physiologic Oxidative Stress
AU - Tothova, Zuzana
AU - Kollipara, Ramya
AU - Huntly, Brian J.
AU - Lee, Benjamin H.
AU - Castrillon, Diego H.
AU - Cullen, Dana E.
AU - McDowell, Elizabeth P.
AU - Lazo-Kallanian, Suzan
AU - Williams, Ifor R.
AU - Sears, Christopher
AU - Armstrong, Scott A.
AU - Passegué, Emmanuelle
AU - DePinho, Ronald A.
AU - Gilliland, D. Gary
N1 - Funding Information:
We thank David Scadden and Lynda Chin for critical review of the manuscript; Jennifer Adelsperger, Rachel Okabe, Sandy Moore, Allison Coburn, and Maricel Gozo for technical assistance; Joe Growney and other members of the Gilliland and DePinho labs for valuable discussion; and John Daley for assistance with flow cytometry. B.J.P.H. is a senior clinical fellow of the Medical Research Council (UK). D.H.C. is a Sidney Kimmel Foundation Scholar and supported by the Mary Kay Ash Foundation. This work was supported in part by NIH grants (D.G.G., R.A.D.) and the Leukemia and Lymphoma Society (D.G.G.). D.G.G. is an Investigator of the Howard Hughes Medical Institute.
PY - 2007/1/26
Y1 - 2007/1/26
N2 - 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.
AB - 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.
KW - DEVBIO
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U2 - 10.1016/j.cell.2007.01.003
DO - 10.1016/j.cell.2007.01.003
M3 - Article
C2 - 17254970
AN - SCOPUS:33846419112
SN - 0092-8674
VL - 128
SP - 325
EP - 339
JO - Cell
JF - Cell
IS - 2
ER -