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Distinct Differentiation-inducing Activities of -Interferon and Cytokine Factors Acting on the Human Promyelocytic Leukemia Cell Line HL-60¹

Cornell University Medical College, Sloan-Kettering Division and the Laboratory of Developmental Hematopolesis, Memorial Sloan-Kettering Cancer Center, New York New York 10021

The human promyelocytic leukemia cell line HL-60 and monoblastic leukemia cell line U937 undergo differentiation when induced by lymphokine and cytokine preparations. Growth inhibition, acquisition of immunoglobulin Fc receptors, increased expression of monocyte-related surface antigens, and an increase in lysosomal enzyme contents accompany maturation induced by -interferon and other cytokine factors tested. Additionally, increased receptors for chemotactic peptide (fMLPR), increased hydrogen peroxide release in response to phorbol myristic acetate stimulation, and the release of prostaglandins (PGE₂ and 6-keto-PGF_1a) follow exposure to lymphokine and cell line sources of myeloid colony-stimulating activity (CSA). -Interferon (-IFN) induced fMLPR in HL-60 (only at 1000 units/ml) but not in U937. Additionally, -IFN did not induce prostaglandin release in either cell line. These myeloid colony-stimulating activity-associated differentiation-inducing factors were obtained from the human heptoma cell line SK-Hep and bladder carcinoma cell line 5637, which were free of interferon activity. The 2-day phytohemagglutinin-induced lymphokine contained no detectable CSA and was a good source of differentiation activity. A simple, rapid assay for a new human CSA with pluripotent hematopoietic stimulating activity (pluripoietin) is described based on stimulation of [³H]glucosamine incorporation. Cell line conditioned media containing pluripoietin, purified pluripoietin, and -IFN are active in this assay. These myeloid leukemia cell line differentiation factors are thus different from interferon and conventional CSA. These results suggest that endogenous human cytokines may have a role in the differentiation of leukemic as well as normal myeloid cells.

¹ This work was supported by the American Cancer Society Grant CH-3F, NIH Grants CA 33484, CA 32516, HL 31780, and K08 CA00966, and the Gar Riechman Foundation.

² To whom requests for reprints should be addressed, at Dept. of Developmental Hematopolesis, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021.

³ Current address: Cetus Corporation, 1400 E. 53rd St., Emeryville, CA 94603.

⁴ Current address: Department of Nutrition, Cook College, P.O. Box 231, Rutgers University, New Brunswick, NJ 08903.

Received 1/ 8/85. Revised 4/ 3/85. Accepted 4/ 5/85.

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