Differentiation and growth modulation of chronic myelogenous leukemia cells by bryostatin.
We have examined the ability of bryostatin 1 (bryo), an activator of protein kinase C, to induce differentiation of chronic myelogenous leukemia (CML) cells obtained from peripheral blood. Bryo induced a prompt and persistent macrophage-like differentiation, as evidenced by functional, morphological, and immunological criteria. Differentiated cells remained viable for at least 21 days with little change in cell number. CML cell cultures treated in semisolid medium with bryo showed diffuse infiltration with single macrophages, as well as discrete macrophage, mixed, and granulocytic colonies. Supernatants of suspension cultures of bryo-treated CML cells contained granulocyte-macrophage colony-stimulating factor (GM-CSF) by enzyme-linked immunosorbent assay. Furthermore, colony formation could be significantly inhibited by the addition of antibodies to GM-CSF. Prolonged liquid culture of CML cells in bryo reduced colony-forming unit, granulocyte-macrophage content. Bryo-induced differentiation was associated with a decrease in lactoferrin, a marker of granulocyte differentiation, and an increase in both c-fms and interleukin-1 beta RNA, both of which are expressed by monocytes/macrophages. These data demonstrate that bryostatin 1 is capable of inducing macrophage-like differentiation in maturing CML cells. Furthermore, bryostatin induces secretion of GM-CSF by such cells in suspension and semisolid medium and also promotes clonal extinction of granulocyte-macrophage progenitors. Bryostatin may be a possible therapeutic agent for CML.
Lilly
M
M
Division of Medical Oncology, University of Washington, Seattle.
Tompkins
C
C
Brown
C
C
Pettit
G
G
Kraft
A
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D054713:Bryostatins; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D007781:Lactoferrin / Q000032:analysis; D007783:Lactones / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D018942:Macrolides; D010587:Phagocytosis; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects* / Q000502:physiology
D000970:Antineoplastic Agents; D054713:Bryostatins; D007783:Lactones; D018942:Macrolides; D012334:RNA, Neoplasm; C046785:bryostatin 1; D007781:Lactoferrin