Genetic reduction of class Ia PI-3 kinase activity alters fetal hematopoiesis and competitive repopulating ability of hematopoietic stem cells in vivo

Laura S. Haneline, Hilary White, Feng Chun Yang, Shi Chen, Christie Orschell, Reuben Kapur, David A. Ingram

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Class IA phosphatidylinositol-3 kinase (PI-3K) is a lipid kinase, which is activated in blood cells by hematopoietic growth factors. In vitro experiments using chemical inhibitors of PI-3K suggest that this kinase is potentially important for hematopoietic stem and progenitor cell (HSC/P) function, and recent studies identify PI-3K as a therapeutic target in treating different leukemias and lymphomas. However, the role of PI-3K in regulating fetal liver or adult hematopoiesis in vivo is unknown. Therefore, we examined PI-3K-deficient embryos generated by a targeted deletion of the p85α and p85β regulatory subunits of PI-3K (p85α-/-p85β +/-). The absolute frequency and number of hematopoietic progenitor cells were reduced in p85α-/- p85β+/- fetal livers compared with wildtype (WT) controls. Further, p85α -/-p85β+/- fetal liver hematopoietic stem cells (HSCs) had decreased multilineage repopulating ability in vivo compared with WT controls in competitive repopulation assays. Finally, purified p85α-/-p85β+/- c-kit+ cells had a decrease in proliferation in response to kit ligand (kitL), a growth factor important for controlling HSC function in vivo. Collectively, these data identify PI-3K as an important regulator of HSC function and potential therapeutic target in treating leukemic stem cells.

Original languageEnglish (US)
Pages (from-to)1375-1382
Number of pages8
JournalBlood
Volume107
Issue number4
DOIs
StatePublished - Feb 15 2006

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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