IP3 3-kinase B controls hematopoietic stem cell homeostasis and prevents lethal hematopoietic failure in mice.

Blood
Sabine SiegemundKarsten Sauer

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 treatmen...Continue Reading

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Citations

Sep 1, 2015·Frontiers in Immunology·Karsten Sauer, Klaus Okkenhaug
Jan 10, 2018·Development·Delong MengJenna L Jewell
Jul 10, 2020·International Journal of Molecular Sciences·Hee Jun ChoHaiyoung Jung
May 22, 2018·Frontiers in Immunology·Mila Elich, Karsten Sauer
Jul 24, 2015·Oncotarget·Stephanie Rigaud, Karsten Sauer
May 14, 2019·The Journal of Clinical Investigation·Chaoyun PanSumin Kang
Nov 8, 2019·Blood·Govindarajan ThangaveluBruce R Blazar
Jan 15, 2021·Proceedings of the National Academy of Sciences of the United States of America·Cuiqing FanYi Zheng
Jun 16, 2021·Journal of Cellular and Molecular Medicine·Huizhong WangYue Lu

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