title: Enhanced ability of daniplestim and myelopoietin-1 to suppress apoptosis in human hematopoietic cells.
abstract: Modified and chimeric cytokines have been developed to aid in the recovery of hematopoietic precursor cells after myeloablative chemotherapy. The interleukin-3 (IL-3) receptor agonist, daniplestim, binds to the IL-3 receptor-alpha subunit with 60-fold greater affinity and induces cell proliferation and colony-forming unit formation 10- to 22-fold better than native IL-3. A chimeric cytokine, myelopoietin-1, composed of daniplestim and a G-CSF receptor agonist binds both the IL-3 and G-CSF receptors. While the in vivo effects of daniplestim and myelopoietin-1 are well described, the mechanisms by which they stimulate growth are not well understood. We have investigated the effects of daniplestim and myelopoietin-1 on the prevention of apoptosis in two human hematopoietic cell lines, OCI-AML.5 and AML 193. Daniplestim and myelopoietin-1 prevented apoptosis to a greater degree than native recombinant IL-3 or G-CSF as determined by annexin V/propidium iodide binding and TUNEL assays. Daniplestim and myelopoietin-1 promoted the maintenance of the mitochondrial membrane potential better than native IL-3 or G-CSF. These cytokines promoted a lower redox potential as higher levels of free radicals were detected after cytokine treatment than in cytokine-deprived cells implying increased respiration. These results indicate that daniplestim and myelopoietin-1 are able to prevent apoptosis in hematopoietic cells more effectively than native IL-3 and G-CSF. These effects of daniplestim and myelopoietin-1 may contribute to their effective ability to repopulate hematopoietic precursor cells after chemotherapy.
authors.affiliation: Department of Microbiology and Immunology, Leo Jenkins Cancer Center, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: McCubrey
authors.forename: W L
authors.initials: WL
authors.lastname: Blalock
authors.forename: O
authors.initials: O
authors.lastname: Saleh
authors.forename: M
authors.initials: M
authors.lastname: Pearce
authors.forename: C
authors.initials: C
authors.lastname: Burrows
authors.forename: L S
authors.initials: LS
authors.lastname: Steelman
authors.forename: J T
authors.initials: JT
authors.lastname: Lee
authors.forename: R A
authors.initials: RA
authors.lastname: Franklin
authors.forename: S M
authors.initials: SM
authors.lastname: Oberhaus
authors.forename: P W
authors.initials: PW
authors.lastname: Moye
authors.forename: P D
authors.initials: PD
authors.lastname: Doshi
authors.forename: J P
authors.initials: JP
authors.lastname: McKearn
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation; D019070:Cell Lineage; D016179:Granulocyte Colony-Stimulating Factor; D006410:Hematopoiesis; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000473:pathology*; D006801:Humans; D007377:Interleukin-3 / Q000031:analogs & derivatives; D010446:Peptide Fragments; D010455:Peptides / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins
chemical_list: D016298:Hematopoietic Cell Growth Factors; D007377:Interleukin-3; D010446:Peptide Fragments; D010455:Peptides; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C404145:myelopoietin; D016179:Granulocyte Colony-Stimulating Factor; C093340:daniplestim