Colony growth of leukemic colony-forming units (L-CFU) obtained from patients with primary acute myelogenous leukemia stimulated with recombinant human interleukin 3 (rh IL-3) is significantly potentiated when recombinant human tumor necrosis factor α (rh TNF-α) is present in cultures. The costimulatory activity of tumor necrosis factor (TNF) α is dose dependent and maximum at TNF-α concentrations of 10 ng/ml. At high density, L-CFU proliferatively respond to TNF-α stimulation in the absence of exogenous rh IL-3. Studies of the mechanism of action of rh TNF-α on acute myelogenous leukemia L-CFU growth suggest that TNF-α acts by inducing release of growth stimulatory hematopoietic cytokines by the leukemic cells themselves, including IL-1α, IL-1β, Granulocyte-macrophage colony-stimulating factor (CSF), granulocyte CSF, and IL-6. Treatment of L-CFU cultures, with neutralizing antibodies to IL-1α, IL-1β, granulocyte-macrophage CSF, granulocyte CSF, and IL-6 to eliminate the endogenous source of these factors is associated with significant inhibition of the synergistic interplay of TNF-α and IL-3.

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Supported by the Mildred Scheel Stiftung (to M. A. B. and F. H.) and the Alexander von Humboldt Stiftung (to Y. A.).

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