PI3 kinase alpha and delta promote hematopoietic stem cell activation

JCI Insight. 2019 May 23;5(13):e125832. doi: 10.1172/jci.insight.125832.


Many cytokines and chemokines that are important for hematopoiesis activate the PI3K signaling pathway. Because this pathway is frequently mutated and activated in cancer, PI3K inhibitors have been developed for the treatment of several malignancies, and are now being tested in the clinic in combination with chemotherapy. However, the role of PI3K in adult hematopoietic stem cells (HSCs), particularly during hematopoietic stress, is still unclear. We previously showed that the individual PI3K catalytic isoforms P110α or P110β have dispensable roles in HSC function, suggesting redundancy between PI3K isoforms in HSCs. We now demonstrate that simultaneous deletion of P110α and P110δ in double knockout (DKO) HSCs uncovers their redundant requirement in HSC cycling after 5-fluorouracil (5-FU) chemotherapy administration. In contrast, DKO HSCs are still able to exit quiescence in response to other stress stimuli, such as LPS. We found that DKO HSCs and progenitors have impaired sensing of inflammatory signals ex vivo, and that levels of IL1-β and MIG are higher in the bone marrow after LPS than after 5-FU administration. Furthermore, exogenous in vivo administration of IL1-β can induce cell cycle entry of DKO HSCs. Our findings have important clinical implications for the use of PI3K inhibitors in combination with chemotherapy.

Keywords: Cell stress; Hematology; Hematopoietic stem cells; Signal transduction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Bone Marrow / drug effects
  • Cell Cycle
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Female
  • Fluorouracil / pharmacology
  • Gene Expression Regulation, Enzymologic
  • Gene Knockout Techniques
  • Hematopoiesis / physiology*
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism*
  • Lipopolysaccharides / adverse effects
  • Male
  • Mice, Knockout
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein Isoforms
  • Signal Transduction / drug effects*


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Lipopolysaccharides
  • Protein Isoforms
  • Class I Phosphatidylinositol 3-Kinases
  • Pik3ca protein, mouse
  • Pik3cd protein, mouse
  • Fluorouracil