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Blood, 15 February 2006, Vol. 107, No. 4, pp. 1375-1382. Prepublished online as a Blood First Edition Paper on October 20, 2005; DOI 10.1182/blood-2005-05-1985. This Article Full Text (PDF) All Versions of this Article: 2005-05-1985v1 107/4/1375    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Haneline, L. S Articles by Ingram, D. A Search for Related Content PubMed PubMed Citation Articles by Haneline, L. S Articles by Ingram, D. A Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 18, 2005 Accepted October 7, 2005 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, and David A Ingram* Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA * Corresponding author; email: dingram{at}iupui.edu. Class IA PI-3 kinase (PI-3K) is a lipid kinase, which is activated in blood cells by hematopoietic growth factors. In vitro experiments utilizing chemical inhibitors of PI-3K suggest that this kinase is potentially important for hematopoietic stem and progenitor (HSC/P) cell 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 p85 and p85 regulatory subunits of PI-3K (p85-/-; p85 +/-). The absolute frequency and number of hematopoietic progenitor cells were reduced in p85 -/-; p85 +/- fetal livers compared to wild-type (WT) controls. Further, p85-/-; p85+/- fetal liver HSCs had decreased multilineage repopulating ability in vivo compared to WT controls in competitive repopulation assays. Finally, purified p85-/-;p85+/- 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y. Zhang, E. Diaz-Flores, G. Li, Z. Wang, Z. Kang, E. Haviernikova, S. Rowe, C.-K. Qu, W. Tse, K. M. Shannon, et al. Abnormal hematopoiesis in Gab2 mutant mice Blood, July 1, 2007; 110(1): 116 - 124. [Abstract] [Full Text] [PDF] H. K. Bone and M. J. Welham Phosphoinositide 3-kinase signalling regulates early development and developmental haemopoiesis J. Cell Sci., May 15, 2007; 120(10): 1752 - 1762. [Abstract] [Full Text] [PDF]

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