Tumor necrosis factor alpha (TNF alpha), as a modulator of hematopoiesis, interacts with many growth factor receptors, such as interleukin-3, granulocyte-macrophage colony-stimulating factor (CSF), and granulocyte-CSF receptors. Here, we studied the interactions between TNF alpha and the stem cell factor (SCF) receptor, c-kit, in normal CD34+ hematopoietic progenitors and their leukemic counterpart, ie, acute myeloid leukemic (AML) CD34+ cells coexpressing c-kit antigen. The results showed that (1) incubation of normal bone marrow mononuclear cells with 200 U/mL rhTNF alpha for 20 hours induced a diminution of 31.2% +/- 5.2% of CD34+ cells coexpressing c-kit; (2) the same decrease was observed using purified CD34+ cells and, furthermore, their proliferative response to SCF was inhibited by 31.5% +/- 7.3% after exposure to TNF alpha; (3) similar experiments performed on CD34+ c-kit+ AML cells from 11 patients gave comparable results. Further analysis at the mRNA level indicated that TNF alpha decreased c-kit mRNA transcripts. Moreover, using monoclonal antibodies against the two types of TNF alpha receptors, p75 and p55, we showed that the downregulation of c-kit proto-oncogene product by TNF alpha, on normal and leukemic CD34+ cells, was exclusively mediated by the TNF alpha p55 receptor. Therefore, we conclude that TNF alpha acts as a downregulator of the SCF receptor expression.
Tumor necrosis factor alpha (TNF alpha) downregulates c-kit proto- oncogene product expression in normal and acute myeloid leukemia CD34+ cells via p55 TNF alpha receptors
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E Khoury, C Andre, S Pontvert-Delucq, B Drenou, C Baillou, M Guigon, A Najman, FM Lemoine; Tumor necrosis factor alpha (TNF alpha) downregulates c-kit proto- oncogene product expression in normal and acute myeloid leukemia CD34+ cells via p55 TNF alpha receptors. Blood 1994; 84 (8): 2506–2514. doi: https://doi.org/10.1182/blood.V84.8.2506.bloodjournal8482506
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