TY - JOUR
T1 - Genetic reduction of class Ia PI-3 kinase activity alters fetal hematopoiesis and competitive repopulating ability of hematopoietic stem cells in vivo
AU - Haneline, Laura S.
AU - White, Hilary
AU - Yang, Feng Chun
AU - Chen, Shi
AU - Orschell, Christie
AU - Kapur, Reuben
AU - Ingram, David A.
PY - 2006/2/15
Y1 - 2006/2/15
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2005-05-1985
DO - 10.1182/blood-2005-05-1985
M3 - Article
C2 - 16239435
AN - SCOPUS:32644433462
SN - 0006-4971
VL - 107
SP - 1375
EP - 1382
JO - Blood
JF - Blood
IS - 4
ER -