title: Cyclic nucleotide-regulated proliferation and differentiation vary in human hematopoietic progenitor cells derived from healthy persons, tumor patients, and chronic myelocytic leukemia patients.
abstract: Although circulating hematopoietic progenitor cells (HPCs) are frequently used in therapeutic approaches, many aspects of their cellular biochemistry are still unclear. In the present study, the effects of cyclic nucleotide-elevating agents on HPC proliferation and differentiation were investigated. HPCs from different sources, including healthy persons, patients with tumors (medulloblastoma, seminoma, or multiple myeloma), and patients with chronic myelocytic leukemia (CML), were compared. HPCs were isolated by standard leukapheresis procedures and analyzed for proliferation and differentiation into the megakaryocytic and granulocytic lineages. HPCs contained high concentrations of cyclic guanosine monophosphate (cGMP)-dependent and cyclic adenosine monophosphate (cAMP)-dependent protein kinases G and A (PKG and PKA, respectively). Whereas PKG was partly down-regulated during culture, the PKA level remained constant. Stimulation of PKG in HPCs isolated from healthy donors or tumor patients resulted in a biphasic reaction: low cGMP concentrations inhibited proliferation and stimulated differentiation into megakaryocytes, whereas high concentrations revealed the opposite effect. In contrast, differentiation into granulocytes was inhibited in a concentration-dependent manner. Stimulation of PKA inhibited HPC differentiation; however, HPC proliferation was inhibited in controls and stimulated in HPCs from tumor patients. HPCs isolated from CML patients showed a nonhomogeneous reaction pattern to both cyclic nucleotides with high variability between the individual donors. We demonstrated the importance of the source of HPCs for the investigation of proliferation and differentiation. Cyclic nucleotide-regulated pathways are clearly involved in HPC proliferation and differentiation. Pharmacological strategies using cyclic nucleotide-elevating substances to influence HPC growth and differentiation in the bone marrow might support current strategies in HPC recovery from the peripheral blood.
authors.affiliation: Institute of Clinical Biochemistry and Pathobiochemistry, University of Wuerzburg, 97080 Wuerzburg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Kobsar
authors.forename: Sonja
authors.initials: S
authors.lastname: Heeg
authors.forename: Katharina
authors.initials: K
authors.lastname: Krohne
authors.forename: Andreas
authors.initials: A
authors.lastname: Opitz
authors.forename: Ulrich
authors.initials: U
authors.lastname: Walter
authors.forename: Markus
authors.initials: M
authors.lastname: Böck
authors.forename: Stepan
authors.initials: S
authors.lastname: Gambaryan
authors.forename: Martin
authors.initials: M
authors.lastname: Eigenthaler
mesh_terms: D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000032:analysis; D017869:Cyclic GMP-Dependent Protein Kinases / Q000032:analysis; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000473:pathology; D006801:Humans; D007937:Leukapheresis; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D008533:Megakaryocytes; D009369:Neoplasms / Q000473:pathology*; D009712:Nucleotides, Cyclic / Q000032:analysis / Q000502:physiology*
chemical_list: D009712:Nucleotides, Cyclic; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases