In Vitro Suppression of Normal Granulocytic Stem Cells by Inhibitory Activity Derived From Human Leukemia Cells 23

Authors:
  • HBHal E. Broxmeyer
    Hal E. Broxmeyer
  • NJNiels Jacobsen
    Niels Jacobsen
  • JKJeffrey Kurland
    Jeffrey Kurland
  • NMNaomi Mendelsohn
    Naomi Mendelsohn
  • MMMalcolm A.S. Moore
    Malcolm A.S. Moore
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Abstract
Extracts and conditioned medium of bone marrow and blood cells from patients with acute leukemia were assayed for activity against granulocyte-monocyte colony-forming cells in agar (CFU-C). Cell extracts from 76 of 85 patients reproducibly inhibited colony formation of normal CFU-C by 28–90%. Leukemia cell-derived Inhibitory activity (LIA) was at a maximum In medium conditioned for 3–4 days with leukemia cells. LlA was against CFU-C during S-phase and had no Influence on production of colony-stimulating activity (CSA) by CSA-produclng cells. No evidence of CSA Inactivation was obtained. LlA was thus different from the previously reported PMN-derived Inhibitory activity which only Inhibits CSA production. Most of the crude LIA was lost at 37° C within 5 hours, but 10 minutes of Incubation with CFU-C resulted in maximum inhibition. Size and cell morphology of colonies surviving LIA were not Influenced. Inhibition of CFUC by leukemia cell extract was observed after 6–8 days but not after 14 days of Incubation. Velocity sedimentation experiments demonstrated that this observation was not due to a reversible effect on sensitive CFU-C. Colonies scored after 14 days were derived from CFU-C not sensitive at the time of treatment but were inhibited by multiple additions of leukemia cell extract. Human marrow cells that form granulocyte colonies In fibrin clot diffusion chambers In mice and pre-CFU-C in suspension culture In vitro were not Inhibited by single and multiple additions of leukemia cell extract. Extracts from normal hematopoietic cells did not inhibit exogenously stimulated colony formation. The results suggest that Inhibition was not nonspecifically toxic and may explain suppression of normal hematopoiesis associated with acute leukemia.