Enhanced ability of danispletim and myelopoietin-1 to suppress apoptosis in human hematopoietic cells

J. A. McCubrey, W. L. Blalock, O. Saleh, M. Pearce, C. Burrows, L. S. Steelman, J. T. Lee, R. A. Franklin, S. M. Oberhaus, P. W. Moye, P. D. Doshi, J. P. McKearn

Research output: Contribution to journalArticlepeer-review

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-α 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.

Original languageEnglish
Pages (from-to)1203-1216
Number of pages14
JournalLeukemia
Volume15
Issue number8
DOIs
Publication statusPublished - 2001

Keywords

  • Apoptosis
  • Cytokines
  • Redox potential
  • Signal transduction

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

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