title: IP3 3-kinase B controls hematopoietic stem cell homeostasis and prevents lethal hematopoietic failure in mice.
abstract: Tight regulation of hematopoietic stem cell (HSC) homeostasis ensures lifelong hematopoiesis and prevents blood cancers. The mechanisms balancing HSC quiescence with expansion and differentiation into hematopoietic progenitors are incompletely understood. Here, we identify Inositol-trisphosphate 3-kinase B (Itpkb) as an essential regulator of HSC homeostasis. Young Itpkb(-/-) mice accumulated phenotypic HSC, which were less quiescent and proliferated more than wild-type (WT) controls. Itpkb(-/-) HSC downregulated quiescence and stemness associated, but upregulated activation, oxidative metabolism, protein synthesis, and lineage associated messenger RNAs. Although they had normal-to-elevated viability and no significant homing defects, Itpkb(-/-) HSC had a severely reduced competitive long-term repopulating potential. Aging Itpkb(-/-) mice lost hematopoietic stem and progenitor cells and died with severe anemia. WT HSC normally repopulated Itpkb(-/-) hosts, indicating an HSC-intrinsic Itpkb requirement. Itpkb(-/-) HSC showed reduced colony-forming activity and increased stem-cell-factor activation of the phosphoinositide-3-kinase (PI3K) effectors Akt/mammalian/mechanistic target of rapamycin (mTOR). This was reversed by treatment with the Itpkb product and PI3K/Akt antagonist IP4. Transcriptome changes and biochemistry support mTOR hyperactivity in Itpkb(-/-) HSC. Treatment with the mTOR-inhibitor rapamycin reversed the excessive mTOR signaling and hyperproliferation of Itpkb(-/-) HSC without rescuing colony forming activity. Thus, we propose that Itpkb ensures HSC quiescence and function through limiting cytokine-induced PI3K/mTOR signaling and other mechanisms.
authors: Department of Immunology and Microbial Science;
authors: Sabine
authors: S
authors: Siegemund
authors: Department of Immunology and Microbial Science;
authors: Stephanie
authors: S
authors: Rigaud
authors: Department of Immunology and Microbial Science;
authors: Claire
authors: C
authors: Conche
authors: Department of Immunology and Microbial Science;
authors: Blake
authors: B
authors: Broaten
authors: Next Generation Sequencing Core; and.
authors: Lana
authors: L
authors: Schaffer
authors: Department of Immunology and Microbial Science;
authors: Luise
authors: L
authors: Westernberg
authors: Next Generation Sequencing Core; and.
authors: Steven Robert
authors: SR
authors: Head
authors: Department of Immunology and Microbial Science; Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA.
authors: Karsten
authors: K
authors: Sauer
mesh_terms: D000740:Anemia / Q000235:genetics* / Q000401:mortality*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006706:Homeostasis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000502:physiology*; D012720:Severity of Illness Index
chemical_list: D017853:Phosphotransferases (Alcohol Group Acceptor); C051038:Inositol 1,4,5-trisphosphate 3-kinase