title: 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.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Tothova
authors.forename: Ramya
authors.initials: R
authors.lastname: Kollipara
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Huntly
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Lee
authors.forename: Diego H
authors.initials: DH
authors.lastname: Castrillon
authors.forename: Dana E
authors.initials: DE
authors.lastname: Cullen
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: McDowell
authors.forename: Suzan
authors.initials: S
authors.lastname: Lazo-Kallanian
authors.forename: Ifor R
authors.initials: IR
authors.lastname: Williams
authors.forename: Christopher
authors.initials: C
authors.lastname: Sears
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Passegué
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001773:Blood Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005786:Gene Expression Regulation / Q000502:physiology; D006410:Hematopoiesis / Q000187:drug effects / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
chemical_list: D000975:Antioxidants; D018797:Cell Cycle Proteins; C108803:FOXO4 protein, human; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C467200:Foxo1 protein, mouse; D017382:Reactive Oxygen Species; D014157:Transcription Factors