title: Resistance of hematopoietic progenitors to Fas-mediated apoptosis is actively sustained by NFκB with a characteristic transcriptional signature.
abstract: Umbilical cord blood (UCB) is a good source of hematopoietic progenitors with increasing implementation in the clinical transplant setting. This study evaluates the molecular mechanisms of progenitor resistance to apoptosis triggered by Fas cross-linking. CD34(+) and lineage-negative progenitors survive short-term ex vivo incubation and are not induced into apoptosis by Fas cross-linking. Furthermore, brief exposure of UCB cells to Fas-ligand for 24-48 h does not impair quantitative severe combine immune deficiency (SCID) reconstitution activity and appears to foster myelomonocyte reconstitution. The transcriptome of Fas receptor-positive CD34(+) cells that survived an apoptotic challenge showed significant transcriptional upregulation of caspase-8, mucosa-associated lymphoid tissue lymphoma translocation gene-1 (MALT1), HtrA2, and GSK3β in addition to higher levels of c-FLICE inhibitory protein (FLIP), Bcl-2, and cytosolic inhibitor of apoptosis protein (cIAP) in all Fas-positive cells. Most prominent is the transcriptional upregulation of several key components the NFκB1 pathway including the membrane receptors TGF-β, interleukin-1 (IL-1), and TCR, the associated factor TNF receptor-associated factor-6 (TRAF6), and the converting enzymes TGF-β-activated kinase-1 (TAK1), double-stranded RNA-activated protein kinase (PKR), and α-catalytic subunit of IκB kinase (IKKα), that promote activation and nuclear translocation of this transcription factor. These data indicate that hematopoietic progenitors are not insensitive to apoptosis but are actively shielded from the extrinsic and intrinsic apoptotic pathways. This may occur through inherent transcriptional upregulation of the entire NFκB pathway in the presence of competent apoptotic signaling.
authors.affiliation: 1 Frankel Laboratory, Center for Stem Cell Research, Schneider Children's Medical Center of Israel , Petach Tikva, Israel .
authors.forename: Keren
authors.initials: K
authors.lastname: Mizrahi
authors.forename: Sivan
authors.initials: S
authors.lastname: Kagan
authors.forename: Jerry
authors.initials: J
authors.lastname: Stein
authors.forename: Isaac
authors.initials: I
authors.lastname: Yaniv
authors.forename: Dov
authors.initials: D
authors.lastname: Zipori
authors.forename: Nadir
authors.initials: N
authors.lastname: Askenasy
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D053222:Fas Ligand Protein / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; D016328:NF-kappa B; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D020169:Caspases