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Ex Vivo Differentiation Therapy as a Method of Leukemic Cell Purging in Murine Bone Marrow Expansion Cultures¹

James Ewing Laboratory of Developmental Hematopoiesis, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

² To whom requests for reprints should be addressed, at DNAX Research Institute of Molecular and Cellular Biology, 901 California Ave., Palo Alto, CA 94304-1104.

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 (-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 -cultures showed that the added stimuli, G-CSF, mutein, and ATRA, decreased the expansion of leukemie 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 -cultures did not result in any impairment of hematopoietic stem cells when measured 5 wk after transplantation.

¹ Supported by USPHS Grants CA-32516, CA-20194, and CA-23766 from the National Cancer Institute; DK 42639 and HL-46546 from the NIH; and the Gar Reichman Fund of the Cancer Research Institute.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 6/11/92. Accepted 9/23/92.

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