Role of mature leukemic cells in the amplification of leukemic stem cells in a murine model.
The recently described PGM-2 leukemia displays a hierarchical structure with bipotential stem cells, B-lymphocyte and macrophage progenitor cells, and post-mitotic end cells. Because the different cell types can easily be identified in vitro by clonal culture assays and simple staining procedures, this leukemia is a useful model for the study of the interactions between different cell compartments in a leukemic clone. Our analysis of the impact of mature leukemic macrophages on the proliferation of stem cells was facilitated by the establishment of long-term cultures producing new stem cells over prolonged periods of time. A prerequisite was the development of an adherent layer of fibroblasts and leukemic macrophages. Enumeration of adherent cells revealed a good correlation between the number of macrophages and the number of stem cells generated, and expansion of the macrophage population by treatment with interleukin 3 (IL-3) resulted in a significant improvement of the culture conditions. Leukemic macrophages were also able to induce the formation of stem-cell colonies in agar culture, suggesting a role for humoral mediators. Antibody neutralization experiments and bioassays identified IL-7 and IL-6 as factors cooperating in the stimulation of stem-cell self-renewal. Feed-back stimulation of leukemic stem cells by mature leukemic cells may also be relevant to human leukemias and have implications for differentiation therapy.
Dührsen
U
U
Abteilung für Onkologie und Hämatologie, Universitätskrankenhaus Eppendorf, Hamburg, Germany.
Knieling
G
G
Hossfeld
D K
DK
D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology*; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells; D002448:Cell Adhesion; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005246:Feedback; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D016298:Hematopoietic Cell Growth Factors / Q000378:metabolism / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D015851:Interleukin-7 / Q000494:pharmacology; D007942:Leukemia, Experimental / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D017077:Culture Media, Conditioned; D016298:Hematopoietic Cell Growth Factors; D007377:Interleukin-3; D015850:Interleukin-6; D015851:Interleukin-7; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins