Glycogen synthase kinase-3beta inhibition preserves hematopoietic stem cell activity and inhibits leukemic cell growth.
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.
Holmes
Tiffany
T
Sydney Cord and Marrow Transplant Facility, Sydney Children's Hospital, Randwick, New South Wales, Australia.
O'Brien
Tracey A
TA
Knight
Robert
R
Lindeman
Robert
R
Shen
Sylvie
S
Song
Emma
E
Symonds
Geoff
G
Dolnikov
Alla
A
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
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