title: A role for the Fas/Fas ligand apoptotic pathway in regulating myeloid progenitor cell kinetics.
abstract: Bone marrow from wild-type mice and mice with mutated Fas (lpr) or mutated Fas ligand (gld) was used to investigate the role of the Fas/FasL system in the regulation of myeloid progenitor cell kinetics.Granulocyte-macrophage colony-forming cells (CFU-GM) were measured by a standard colony assay and the proliferative activity of CFU-GM was measured by replating primary colonies and observing secondary colony formation. Fas expression was restored to lpr mouse bone marrow cells by retrovirus-mediated gene transfer and gld mouse marrow cells were treated with soluble FasL. Wild-type marrow cells were treated with YVAD (a caspase inhibitor) or anti-Fas monoclonal antibodies. There were greater frequencies of myeloid progenitor cells (CFU-GM) in lpr and gld mouse marrow compared to wild-type (WT) marrow (p = 0.0008). The proliferative capacity of CFU-GM was also significantly greater for lpr and gld CFU-GM compared to WT CFU-GM (p = 0.0003 and 0.0001, respectively). Retrovirus-mediated restoration of Fas into lpr marrow, and provision of soluble FasL (sFasL) to gld CFU-GM reduced CFU-GM proliferation to WT levels. Treatment of WT CFU-GM with YVAD or anti-FasL monoclonal antibody increased CFU-GM proliferation to the levels found in lpr and gld CFU-GM. YVAD significantly increased and anti-Fas significantly reduced the proliferative capacity of human CFU-GM (p = 0.015 and 0.04, respectively).Fas, FasL, and caspase activation may play an important role in regulating myeloid progenitor cell kinetics.
authors.affiliation: LRF Centre For Adult Leukaemia, Department of Haematology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Campus, DuCane Road, London W12 0NN, UK.
authors.forename: Faris Q B
authors.initials: FQ
authors.lastname: Alenzi
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Marley
authors.forename: John L
authors.initials: JL
authors.lastname: Lewis
authors.forename: Anil
authors.initials: A
authors.lastname: Chandrashekran
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Warrens
authors.forename: John M
authors.initials: JM
authors.lastname: Goldman
authors.forename: Myrtle Y
authors.initials: MY
authors.lastname: Gordon
mesh_terms: D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D053222:Fas Ligand Protein; D006801:Humans; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D023461:Myeloid Progenitor Cells / Q000166:cytology* / Q000378:metabolism; D014161:Transduction, Genetic; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019014:fas Receptor; D020169:Caspases