title: Glycogen synthase kinase-3beta inhibition preserves hematopoietic stem cell activity and inhibits leukemic cell growth.
abstract: Ex vivo expansion of cord blood cells generally results in reduced stem cell activity in vivo. Glycogen synthase kinase-3beta (GSK-3beta) regulates the degradation of beta-catenin, a critical regulator of hematopoietic stem cells (HSCs). Here we show that GSK-3beta inhibition activates beta-catenin in cord blood CD34(+) cells and upregulates beta-catenin transcriptional targets c-myc and HoxB4, both known to regulate HSC self-renewal. GSK-3beta inhibition resulted in delayed ex vivo expansion of CD34(+) cells, yet enhanced the preservation of stem cell activity as tested in long-term culture with bone marrow stroma. Delayed cell cycling, reduced apoptosis, and increased adherence of hematopoietic progenitor cells to bone marrow stroma were observed in these long-term cultures treated with GSK-3beta inhibitor. This improved adherence to stroma was mediated via upregulation of CXCR4. In addition, GSK-3beta inhibition preserved severe combined immunodeficiency (SCID) repopulating cells as tested in the nonobese diabetic/SCID mouse model. Our data suggest the involvement of GSK-3beta inhibition in the preservation of HSC and their interaction with the bone marrow environment. Methods for the inhibition of GSK-3beta may be developed for clinical ex vivo expansion of HSC for transplantation. In addition, GSK-3beta inhibition suppressed leukemic cell growth via the induction of apoptosis mediated by the downregulation of survivin. Modulators of GSK-3beta may increase the range of novel drugs that specifically kill leukemic cells while sparing normal stem cells.
authors.affiliation: Sydney Cord and Marrow Transplant Facility, Sydney Children's Hospital, Randwick, New South Wales, Australia.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Holmes
authors.forename: Tracey A
authors.initials: TA
authors.lastname: O'Brien
authors.forename: Robert
authors.initials: R
authors.lastname: Knight
authors.forename: Robert
authors.initials: R
authors.lastname: Lindeman
authors.forename: Sylvie
authors.initials: S
authors.lastname: Shen
authors.forename: Emma
authors.initials: E
authors.lastname: Song
authors.forename: Geoff
authors.initials: G
authors.lastname: Symonds
authors.forename: Alla
authors.initials: A
authors.lastname: Dolnikov
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D036101:Cord Blood Stem Cell Transplantation; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007938:Leukemia / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D010091:Oximes / Q000494:pharmacology; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014470:Umbilical Cord / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D051176:beta Catenin / Q000378:metabolism
chemical_list: C483321:6-bromoindirubin-3'-oxime; D018952:Antigens, CD34; D007211:Indoles; D010091:Oximes; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3