Progenipoietins

Biological characterization of a family of dual agonists of fetal liver tyrosine kinase-3 and the granulocyte colony-stimulating factor receptor

Philip Streeter, N. I. Minster, L. E. Kahn, W. F. Hood, L. E. Vickery, T. L. Thurman, J. B. Monahan, J. K. Welply, J. P. McKearn, S. L. Woulfe

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Objective: The progenipoietins, a class of engineered proteins containing both fetal liver tyrosine kinase-3 and granulocyte colony-stimulating factor receptor agonist activities, were functionally characterized in vitro and in vivo. Materials and Methods: Four representative progenipoietins were evaluated for receptor binding, receptor-dependent cell proliferation, colony-forming unit activity, and their effects on hematopoiesis in the C57BL/6 mouse. Results: The progenipoietins bound to fetal liver tyrosine kinase-3 and the granulocyte colony-stimulating factor receptor with affinities within twofold to threefold of the native ligands, and each progenipoietin bound simultaneously to both fetal liver tyrosine kinase-3 and the granulocyte colony-stimulating factor receptor. The progenipoietins exhibited different levels of activity in receptor-dependent cell proliferation assays. The fetal liver tyrosine kinase-3-dependent cell proliferation activity of three of four progenipoietins was decreased sixfold to 33-fold relative to native fetal liver tyrosine kinase-3 ligand, while granulocyte colony-stimulating factor receptor-dependent activity of the progenipoietins was within twofold to threefold of native granulocyte colony-stimulating factor. At nonsaturating concentrations, the progenipoietins stimulated colony formation to a greater extent than the equimolar combination of fetal liver tyrosine kinase-3 and granulocyte colony-stimulating factor. Treatment of mice with the progenipoietins yielded dramatic increases in peripheral blood and splenic white blood cells, polymorphonuclear leukocytes, and dendritic cells. Conclusion: These preclinical results demonstrate that the progenipoietins are potent hematopoietic growth factors that stimulate cells in a receptor-dependent manner. When administered in vivo, the progenipoietins effectively promote the generation of multiple cell lineages. Thus, in both in vitro and in vivo settings, the progenipoietins as single molecules exhibit the synergistic activity of the combination of fetal liver tyrosine kinase-3 and granulocyte colony-stimulating factor.

Original languageEnglish (US)
Pages (from-to)41-50
Number of pages10
JournalExperimental Hematology
Volume29
Issue number1
DOIs
StatePublished - 2001
Externally publishedYes

Fingerprint

fms-Like Tyrosine Kinase 3
Granulocyte Colony-Stimulating Factor Receptors
Protein-Tyrosine Kinases
Granulocyte Colony-Stimulating Factor
Cell Proliferation
Hematopoietic Cell Growth Factors
Ligands
Hematopoiesis
Cell Lineage
Inbred C57BL Mouse
Dendritic Cells
Neutrophils
Leukocytes
Stem Cells

Keywords

  • Dendritic cells
  • Fetal liver tyrosine kinase-3 ligand
  • Granulocyte colony-stimulating factor
  • Hematopoietic growth factors
  • Progenipoietin

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

Cite this

Progenipoietins : Biological characterization of a family of dual agonists of fetal liver tyrosine kinase-3 and the granulocyte colony-stimulating factor receptor. / Streeter, Philip; Minster, N. I.; Kahn, L. E.; Hood, W. F.; Vickery, L. E.; Thurman, T. L.; Monahan, J. B.; Welply, J. K.; McKearn, J. P.; Woulfe, S. L.

In: Experimental Hematology, Vol. 29, No. 1, 2001, p. 41-50.

Research output: Contribution to journalArticle

Streeter, P, Minster, NI, Kahn, LE, Hood, WF, Vickery, LE, Thurman, TL, Monahan, JB, Welply, JK, McKearn, JP & Woulfe, SL 2001, 'Progenipoietins: Biological characterization of a family of dual agonists of fetal liver tyrosine kinase-3 and the granulocyte colony-stimulating factor receptor', Experimental Hematology, vol. 29, no. 1, pp. 41-50. https://doi.org/10.1016/S0301-472X(00)00616-0
Streeter, Philip ; Minster, N. I. ; Kahn, L. E. ; Hood, W. F. ; Vickery, L. E. ; Thurman, T. L. ; Monahan, J. B. ; Welply, J. K. ; McKearn, J. P. ; Woulfe, S. L. / Progenipoietins : Biological characterization of a family of dual agonists of fetal liver tyrosine kinase-3 and the granulocyte colony-stimulating factor receptor. In: Experimental Hematology. 2001 ; Vol. 29, No. 1. pp. 41-50.
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T2 - Biological characterization of a family of dual agonists of fetal liver tyrosine kinase-3 and the granulocyte colony-stimulating factor receptor

AU - Streeter, Philip

AU - Minster, N. I.

AU - Kahn, L. E.

AU - Hood, W. F.

AU - Vickery, L. E.

AU - Thurman, T. L.

AU - Monahan, J. B.

AU - Welply, J. K.

AU - McKearn, J. P.

AU - Woulfe, S. L.

PY - 2001

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N2 - Objective: The progenipoietins, a class of engineered proteins containing both fetal liver tyrosine kinase-3 and granulocyte colony-stimulating factor receptor agonist activities, were functionally characterized in vitro and in vivo. Materials and Methods: Four representative progenipoietins were evaluated for receptor binding, receptor-dependent cell proliferation, colony-forming unit activity, and their effects on hematopoiesis in the C57BL/6 mouse. Results: The progenipoietins bound to fetal liver tyrosine kinase-3 and the granulocyte colony-stimulating factor receptor with affinities within twofold to threefold of the native ligands, and each progenipoietin bound simultaneously to both fetal liver tyrosine kinase-3 and the granulocyte colony-stimulating factor receptor. The progenipoietins exhibited different levels of activity in receptor-dependent cell proliferation assays. The fetal liver tyrosine kinase-3-dependent cell proliferation activity of three of four progenipoietins was decreased sixfold to 33-fold relative to native fetal liver tyrosine kinase-3 ligand, while granulocyte colony-stimulating factor receptor-dependent activity of the progenipoietins was within twofold to threefold of native granulocyte colony-stimulating factor. At nonsaturating concentrations, the progenipoietins stimulated colony formation to a greater extent than the equimolar combination of fetal liver tyrosine kinase-3 and granulocyte colony-stimulating factor. Treatment of mice with the progenipoietins yielded dramatic increases in peripheral blood and splenic white blood cells, polymorphonuclear leukocytes, and dendritic cells. Conclusion: These preclinical results demonstrate that the progenipoietins are potent hematopoietic growth factors that stimulate cells in a receptor-dependent manner. When administered in vivo, the progenipoietins effectively promote the generation of multiple cell lineages. Thus, in both in vitro and in vivo settings, the progenipoietins as single molecules exhibit the synergistic activity of the combination of fetal liver tyrosine kinase-3 and granulocyte colony-stimulating factor.

AB - Objective: The progenipoietins, a class of engineered proteins containing both fetal liver tyrosine kinase-3 and granulocyte colony-stimulating factor receptor agonist activities, were functionally characterized in vitro and in vivo. Materials and Methods: Four representative progenipoietins were evaluated for receptor binding, receptor-dependent cell proliferation, colony-forming unit activity, and their effects on hematopoiesis in the C57BL/6 mouse. Results: The progenipoietins bound to fetal liver tyrosine kinase-3 and the granulocyte colony-stimulating factor receptor with affinities within twofold to threefold of the native ligands, and each progenipoietin bound simultaneously to both fetal liver tyrosine kinase-3 and the granulocyte colony-stimulating factor receptor. The progenipoietins exhibited different levels of activity in receptor-dependent cell proliferation assays. The fetal liver tyrosine kinase-3-dependent cell proliferation activity of three of four progenipoietins was decreased sixfold to 33-fold relative to native fetal liver tyrosine kinase-3 ligand, while granulocyte colony-stimulating factor receptor-dependent activity of the progenipoietins was within twofold to threefold of native granulocyte colony-stimulating factor. At nonsaturating concentrations, the progenipoietins stimulated colony formation to a greater extent than the equimolar combination of fetal liver tyrosine kinase-3 and granulocyte colony-stimulating factor. Treatment of mice with the progenipoietins yielded dramatic increases in peripheral blood and splenic white blood cells, polymorphonuclear leukocytes, and dendritic cells. Conclusion: These preclinical results demonstrate that the progenipoietins are potent hematopoietic growth factors that stimulate cells in a receptor-dependent manner. When administered in vivo, the progenipoietins effectively promote the generation of multiple cell lineages. Thus, in both in vitro and in vivo settings, the progenipoietins as single molecules exhibit the synergistic activity of the combination of fetal liver tyrosine kinase-3 and granulocyte colony-stimulating factor.

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KW - Hematopoietic growth factors

KW - Progenipoietin

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