title: Small-molecule inhibitor of glycogen synthase kinase 3β 6-Bromoindirubin-3-oxime inhibits hematopoietic regeneration in stem cell recipient mice.
abstract: Small-molecule inhibitors of glycogen synthase kinase 3β (GSK3β) have demonstrated strong anti-leukemia effects in preclinical studies. Here, we investigated the effect of GSK3β inhibitor 6-Bromoindirubin-3-oxime (BIO) previously shown to inhibit leukemia cell growth in vitro and of animal models on hematopoietic regeneration in recipients of stem cell transplant. BIO administered to immunocompromised mice transplanted with human hematopoietic stem cells inhibited human stem cell engraftment in the bone marrow (BM) and peripheral blood. BIO reduced CD34(+) progenitor cells in the BM, and primitive lymphoid progenitors re-populated host thymus at later stages post-transplant. The development of all T-cell subsets in the thymus was suppressed in BIO-treated mice. Human cell engraftment was gradually restored after discontinuation of BIO treatment; however, T-cell depletion remained until the end of experiment, which correlated with the attenuated thymic function in the host. BIO delayed CD34(+) cell expansion in stroma-supported or cytokine-only cultures. BIO treatment delayed progenitor cell divisions and induced apoptosis in cultures with sub-optimal cytokine support. In addition, BIO inhibited B- and T-cell development in co-cultures with MS5 and OP9-DL1 BM stroma cells, respectively. These data suggest that administration of GKS3β inhibitors may act to delay hematopoietic regeneration in patients who received stem cell transplant.
authors.affiliation: 1 Sydney Cord and Marrow Transplant Facility, Centre for Children's Cancer and Blood Disorders, Sydney Children's Hospital , Sydney, Australia .
authors.forename: Sylvie
authors.initials: S
authors.lastname: Shen
authors.forename: Ning
authors.initials: N
authors.lastname: Xu
authors.forename: Guy
authors.initials: G
authors.lastname: Klamer
authors.forename: Kap-Hyoun
authors.initials: KH
authors.lastname: Ko
authors.forename: Melissa
authors.initials: M
authors.lastname: Khoo
authors.forename: David
authors.initials: D
authors.lastname: Ma
authors.forename: John
authors.initials: J
authors.lastname: Moore
authors.forename: Tracey A
authors.initials: TA
authors.lastname: O'Brien
authors.forename: Alla
authors.initials: A
authors.lastname: Dolnikov
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010091:Oximes / Q000494:pharmacology*
chemical_list: C483321:6-bromoindirubin-3'-oxime; D007211:Indoles; D010091:Oximes; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3