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Relationship of Acivicin-induced Monocytoid Differentiation of Human Myeloid Leukemia Cells to Acivicin-induced Modulation of Growth Factor, Cytokine, and Protooncogene mRNA Expression¹

VA and Duke University Medical Centers, Division of Hematology/Oncology, Durham, North Carolina 27705

We have previously noted that the glutamine antagonist acivicin (S,5S--amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid) induces monocytoid differentiation of freshly isolated human myeloid leukemia cells and HL-60 cells. This study was designed to determine the effects of acivicin on the levels of HL-60 cell mRNA transcripts of several cytokines, growth factors, and protooncogenes implicated in the control of hematopoietic cell proliferation and differentiation. Control HL-60 cells did not express mRNA for granulocyte-colony-stimulating factor, granulocyte-macrophage-colony-stimulating factor, interleukin 3, or interleukin 6, and acivicin or phorbol myristate acetate did not induce their expression. Phorbol myristate acetate reduced expression of c-myc, c-myb, and heat shock protein 70 and enhanced those of macrophagecolony-stimulating factor and c-fms. Acivicin caused a decreased expression of c-myc, and an increased expression of mRNA for interleukin 1ß and tumor necrosis factor (TNF-). The drug also caused an initial increase in c-myb, followed by a subsequent decrease below baseline levels. Supernatants and lysates of acivicin-treated HL-60 cells contained increased levels of interleukin 1ß. Both TNF- and interleukin 1ß have been shown previously to influence hematopoietic cell differentiation. In our experiments, exogenous interleukin 1 added to HL-60 cells did not induce differentiation, but the combination of interleukin 1 and TNF synergistically enhanced the process. Pretreatment of the cells with TNF enhanced their responsiveness to subsequent treatment with interleukin 1. Our results demonstrate that the glutamine antagonist acivicin modulates HL-60 cell expression of TNF-, interleukin 1ß, c-myc, and c-myb and suggest that interleukin 1ß and TNF- might (in an autocrine manner) cause the differentiation.

¹ This work was supported in part by the VA Research Service, the James Swiger Hematology Research Fund, and Grants P01 AI23308, P01 32682, and P50 AR39162 from the NIH.

² To whom requests for reprints should be addressed, at VA and Duke University Medical Centers, 151G, Durham, NC 27705.

Received 7/11/90. Accepted 12/ 3/90.