Ex vivo differentiation therapy as a method of leukemic cell purging in murine bone marrow expansion cultures.
We investigated the use of differentiation therapy as a method of purging bone marrow (BM) of leukemic cells in ex vivo murine BM expansion cultures (delta-cultures). In clonal cultures and in suspension cultures a combination of the differentiation-inducing agents granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-6, and all-trans-retinoic acid (ATRA) was found to be most effective in inducing the differentiation of the murine myelomonocytic leukemic cell line WEHI 3B D+ LacZ clone 2.8 (clone 2.8). Furthermore, we investigated the activity of a mutant form of IL-6, mutein, and found it to have a greater specific activity in cell proliferation assays and in a clone 2.8 differentiation assay than the native form of IL-6. Coculture of clone 2.8 and BM in IL-1 and kit-ligand-stimulated delta-cultures showed that the added stimuli, G-CSF, mutein, and ATRA, decreased the expansion of leukemic cells. Mice transplanted with G-CSF, mutein, and ATRA-purged BM had an increased survival time relative to nonpurged controls. The addition of G-CSF, mutein, and ATRA to delta-cultures did not result in any impairment of hematopoietic stem cells when measured 5 wk after transplantation.
Muench
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James Ewing Laboratory of Developmental Hematopoiesis, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Guy
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Moore
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MA
D000818:Animals; D016465:Bone Marrow Purging / Q000379:methods*; D002454:Cell Differentiation / Q000187:drug effects*; D002999:Clone Cells; D003114:Colony-Forming Units Assay; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D016298:Hematopoietic Cell Growth Factors; D015850:Interleukin-6; D051379:Mice; D008807:Mice, Inbred BALB C; D019089:Stem Cell Factor; D014212:Tretinoin; D014407:Tumor Cells, Cultured
D016298:Hematopoietic Cell Growth Factors; D015850:Interleukin-6; D019089:Stem Cell Factor; D016179:Granulocyte Colony-Stimulating Factor; D014212:Tretinoin