title: MCP-1, not MIP-1alpha, is the endogenous chemokine that cooperates with TGF-beta to inhibit the cycling of primitive normal but not leukemic (CML) progenitors in long-term human marrow cultures.
abstract: The long-term culture (LTC) system has been useful for analyzing mechanisms by which stromal cells regulate the proliferative activity of primitive normal, but not chronic myeloid leukemia (CML), hematopoietic progenitor cells. In previous studies, we identified two endogenous inhibitors in this system. One is transforming growth factor-beta (TGF-beta), which is equally active on primitive normal and CML progenitors. The other we now show to be monocyte chemoattractant protein-1 (MCP-1). Thus, MCP-1, when added to LTC, blocked the activation of primitive normal progenitors but did not arrest the cycling of primitive CML progenitors. Moreover, the endogenous inhibitory activity of LTC stromal layers could be overcome by the addition of neutralizing antibodies to MCP-1, but not to macrophage inflammatory protein-1alpha (MIP-1alpha). However, neither of these antibodies antagonized the inhibitory activity of NAc-Ser-Asp-Lys-Pro (AcSDKP) on primitive normal but not CML progenitor cycling in this system. Moreover, none of six other -C-C- or -C-X-C- chemokines, previously shown to inhibit primitive normal human CFC proliferation in semisolid assays, were found to act as negative regulators when added to normal LTC. These results provide further support for the concept that primitive CML progenitor cell proliferation is deregulated when these cells are exposed to limiting concentrations of multiple inhibitors, only some of which have differential actions on normal and Ph+/BCR-ABL+ cells.
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency and the Departments of Medical Genetics, Medicine, and Pathology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: J D
authors.initials: JD
authors.lastname: Cashman
authors.forename: C J
authors.initials: CJ
authors.lastname: Eaves
authors.forename: A H
authors.initials: AH
authors.lastname: Sarris
authors.forename: A C
authors.initials: AC
authors.lastname: Eaves
mesh_terms: D001853:Bone Marrow / Q000473:pathology*; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000494:pharmacology / Q000502:physiology*; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000502:physiology; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D017154:Stromal Cells / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines; D019402:Macrophage Inflammatory Proteins; D009842:Oligopeptides; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D016044:Fusion Proteins, bcr-abl; C058504:goralatide