Authors:
Sabine Siegemund, Stephanie Rigaud, Claire Conche, Blake Broaten, Lana Schaffer, Luise Westernberg, Steven Robert Head, and Karsten Sauer
Summary:
Tight regulation of hematopoietic stem cell (HSC) homeostasis ensures life-long hematopoiesis and prevents blood cancers. The mechanisms balancing HSC quiescence with expansion and differentiation into hematopoietic progenitors are incompletely understood. Here, we identify inositoltrisphosphate (IP3) 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 wildtype controls. Itpkb-/- HSC downregulated quiescence and stemness associated, but upregulated activation, oxidative metabolism, protein synthesis and lineage associated mRNAs. 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. Wildtype HSC normally repopulated Itpkb-/- hosts, indicating a 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/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.
Source:
Blood; (03/18/15)